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  • 1.
    Adolfsson, Per
    et al.
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Ahlstrand, Christer
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Urologi. Linköpings universitet, Hälsouniversitetet.
    Varenhorst, Eberhard
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Urologi. Linköpings universitet, Hälsouniversitetet.
    Svensson, Samuel
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Lysophosphatidic acid stimulates proliferation of cultured smooth muscle cells from human BPH tissue: Sildenafil and papaverin generate inhibition2002Ingår i: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 51, nr 1, s. 50-58Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background The endogenous substance lysophosphatidic acid (LPA) has been found to generate proliferation of cultured smooth muscle cells (SMC). Therefore, the effect of LPA on human benign prostate hyperplasia (BPH) could be of interest.

    Methods The proliferative effect of LPA on cultured human prostatic SMC from specimens obtained at trans-urethral resection of the prostate (TURP) because of BPH, was analyzed by [3H]-thymidine and [35S]-methionine incorporation. In addition, LPA stimulated BPH SMC were treated with papaverin, forskolin, sildenafil or zaprinast, well known to increase the intracellular level of cAMP or cGMP.

    Results LPA produced a dose-dependent increase in BPH SMC, both regarding DNA- and protein-synthesis with EC50 values of 3 and 10 μM, respectively. Furthermore, both papaverin, a general phosphodiesterase inhibitor regarding cAMP hydrolyzes, and forskolin, an adenylyl cyclase stimulating agent, inhibited the LPA-stimulated DNA replication in a dose dependent manner with IC50  = 2.5, and 0.35 μM, respectively. cGMP increasing agents, such as the NO-donors SIN-1 and SNAP, produced a weak anti-proliferative response. However, both phosphodiesterase 5 inhibitors sildenafil (Viagra®) and zaprinast efficiently blocked DNA replication. In addition, when the protein synthesis was examined, we found that the LPA response was significantly inhibited by forskolin and papaverin.

    Conclusions The major conclusion of this investigation is that the endogenous serum component LPA, is able to promote human BPH SMC growth. In addition, our study indicates that cyclic nucleotides can inhibit this effect. Future clinical studies will be needed to determine if different specific phosphodiesterase inhibitors per se or in combination could represent a new therapeutic possibility for the treatment of BPH.

  • 2.
    Adolfsson, Per
    et al.
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Haug, Ingrid
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Berg, Göran
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Obstetrik och gynekologi. Linköpings universitet, Hälsouniversitetet.
    Svensson, Samuel
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Changes in β2-adrenoceptor expression and in adenylyl cyclase and phosphodiesterase activity in human uterine leiomyomas2000Ingår i: Molecular human reproduction, ISSN 1360-9947, E-ISSN 1460-2407, Vol. 6, nr 9, s. 835-842Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Uterine leiomyoma is a very common benign tumour with unclear pathophysiology in adult women. In the present study we have investigated the expression level of α2- and β2-adrenoceptors, and the adenylyl cyclase and phosphodiesterase activity in leiomyoma tissue compared with adjacent myometrium. Our results show that the α22-adrenoceptor ratio is increased in leiomyoma, due to a significant decrease in β2-adrenoceptor expression. These changes were not due to an increased innervation, as the tumour tissue was completely devoid of nerve fibres. Moreover, the adenylyl cyclase activity of leiomyoma membranes was found to be ~50% lower, whereas the phosphodiesterase activity was significantly increased (by ~100%). We found that stimulating an increase in intracellular cyclic AMP, by adenylyl cyclase activity through β2-adrenoceptors (isoprenaline), by direct enzyme activation (forskolin), or by inhibition of phosphodiesterase activity (papaverine), potently blocked both protein and DNA synthesis in cultured leiomyoma smooth muscle cells. Our results imply the adrenoceptors might be involved in, or a consequence of, leiomyoma growth. The results also suggest a new interesting approach for leiomyoma pharmacotherapy.

  • 3.
    Adolfsson, Per I.
    et al.
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Ahlstrand, Christer
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Urologi. Linköpings universitet, Hälsouniversitetet.
    Varenhorst, Eberhard
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Urologi. Linköpings universitet, Hälsouniversitetet.
    Hultgren, Sitti
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Svensson, Samuel P. S.
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Characterization of EDG receptor expression and proliferative response in cultured human BPH smooth muscle cellsManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    The endogenous phospholipids, lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) are both known to generate a Vvide variety of effects in various cell systems by the endothelial differentiation gene (Edg) receptor family, including 7 different G-protein coupled Edg receptors.

    In this study, expression of LPA- and SlP Edg receptors was examined, and so was the effect with respect to proliferation on cultured BPH smooth muscle cells smc. Mmeover, theresponse on cAMP levels was examined. Finally, a potential link between activation of the MAP kinase cascade and the LPA stimulated proliferation was investigated.

    First, the RT-PCR analysis of the Edg receptors in BPH smc, demonstrated a heterogeneous expression including all receptors except the Edg6 subtype. Further, in contrast to LPA, the mitogen effect of SIP, demonstrated a concentration-dependent biphasic response, including stimulation below 1μM, whereas inhibition was obtained at higher concentrations. Forskolin induced a rapid and transient cAMP response in LPA stimulated cells, with a peak-value after 3 minutes. After 15 minutes the cAMP level had retmned to base-line level. However a gradual increase to 15% of maximum value was obtained after additional 30 minutes, and thereafter a gradual reduction was observed. The mentioned antiproliferative response generated by SIP could not be conelated to an intracellular cAMP increase. Finally, when the LPA treated smc was co-incubated with the MAPK kinase inhibitor PD98059 (10 μM) the mitogen response was eliminated.

    The cAIVIP increase, which was induced by forskolin, corresponds with mentioned antiproliferative effect whereas a similar con-elation was not obtained regarding SIP. The intracellular signal mechanisms triggered by LPA and S1P in BPH smc remain to be further investigated.

  • 4.
    Adolfsson, Per I
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet.
    Bloth, Björn
    Department of Clinical Neuroscience, Laboratory of Translational Neuropharmacology, Center of Molecular Medicine, Karolinska Institute, Stockholm, Sweden.
    Hägg, Staffan
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Region Östergötland, Diagnostikcentrum, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Futurum Academy for Health and Care, Jönköping County Council, Sweden.
    Svensson, Samuel P S
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet.
    Zinc Induces a Bell-shaped Proliferative Dose-response Effect in Cultured Smooth Muscle Cells From Benign Prostatic Hyperplasia.2015Ingår i: Urology, ISSN 0090-4295, E-ISSN 1527-9995, Vol. 85, nr 3, s. 704.e15-704.e19Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE: To investigate the effects of zinc (Zn(2+)) concentrations on cultured benign prostatic hyperplasia (BPH) smooth muscle cell (SMC) proliferation.

    METHODS: The effects of Zn(2+) were studied in primary cultures of human BPH SMC, stimulated with either 10-μM lysophosphatidic acid (LPA) or LPA in combination with 100-nM testosterone. Deoxyribonucleic acid replication and protein synthesis using [(3)H]-thymidine and [(35)S]-methionine incorporation were measured. Furthermore, studies were performed to evaluate if Zn(2+) could potentiate the inhibitory effect of phosphodiesterase-5 blockers, on BPH SMC proliferation.

    RESULTS: Zn(2+) generated a bell-shaped concentration response, both regarding deoxyribonucleic acid replication and protein synthesis in cultured BPH SMC. Below a threshold value (approximately 200 μM), a significant mitogenic effect was seen, whereas higher concentrations inhibited SMC proliferation after stimulation with LPA. This effect was even more pronounced after stimulation of LPA in combination with testosterone. Moreover, phosphodiesterase-5 inhibitors, that is, sildenafil blocked LPA-stimulated BPH SMC proliferation. This antiproliferative effect, was significantly potentiated by coincubation with Zn(2+) in an additative manner.

    CONCLUSION: The bell-shaped concentration response of Zn(2+) on cultured BPH SMC proliferation suggests that changes in prostate Zn(2+) concentrations, during aging, diet, or inflammatory conditions, may be of importance in the pathogenesis of BPH.

  • 5.
    Adolfsson, Per I.
    et al.
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Dahle, Lars Olav
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Obstetrik och gynekologi. Linköpings universitet, Hälsouniversitetet.
    Berg, Göran
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Obstetrik och gynekologi. Linköpings universitet, Hälsouniversitetet.
    Svensson, Samuel P. S.
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Characterization of α2-Adrenoceptor Subtypes in Pregnant Human Myometrium1998Ingår i: Gynecologic and Obstetric Investigation, ISSN 0378-7346, E-ISSN 1423-002X, Vol. 45, nr 3, s. 145-150Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The aim of the present investigation was to determine which subtypes of the α2-adrenoceptors are being expressed in the human pregnant myometrium at term pregnancy. In radioligand binding studies, the specific binding of [3H]rauwolscine to human myometrial membranes was specific and of high affinity with Kd of 2.8 ± 0.6 nM and Bmax of 95 ± 5 fmol/mg protein. Results from competition for the binding of [3H]rauwolscine using subtype-selective ligands, oxymetazoline (α2A-subptype), chlorpromazine (α2B-subtype) and prazosin (α2B-α2C-subtype), suggested that the α2A- and α2B-subtypes are being co-expressed. In order to examine if also the α2C-subtype is being expressed we used an optimal concentration of oxymetazoline or chlorpromazine which would block the high-affinity site, equivalent to the α2A- and α2B-subtype respectively. Competition curves of both oxymetazoline and chlorpromazine still showed a significantly better fit using a two-site model, suggesting that the α2C-subtype also is being expressed. The expression of α2C-subtype mRNA was confirmed using reverse transcription-polymerase chain reaction on mRNA isolated from myometrial biopsies.

    In conclusion, our results suggest that all three subtypes of α2-adrenoceptors are being coexpressed in the human myometrium at term pregnancy and that α2-expression is dominated by the α2A-subtype.

  • 6. Aifa, Sami
    et al.
    Johansen, Knut
    Nilsson, Ulrica K
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Liedberg, Bo
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Sensorvetenskap och Molekylfysik. Linköpings universitet, Tekniska högskolan.
    Lundström, Ingemar
    Svensson, Samuel
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Interactions between the juxtamembrane domain of the EGFR and calmodulin measured by surface plasmon resonance2002Ingår i: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 14, nr 12, s. 1005-1013Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    One early response to epidermal growth factor receptor (EGFR) activation is an increase in intracellular calcium. We have used surface plasmon resonance (SPR) to study real-time interactions between the intracellular juxtamembrane (JM) region of EGFR and calmodulin. The EGFR-JM (Met644-Phe688) was expressed as a GST fusion protein and immobilised on a sensor chip surface. Calmodulin specifically interacts with EGFR-JM in a calcium-dependent manner with a high on and high off rate. Chemical modification of EGFR-JM by using arginine-selective phenylglyoxal or deletion of the basic segment Arg645-Arg657 inhibits the interaction. Phosphorylation of EGFR-JM by protein kinase C (PKC) or glutamate substitution of Thr654 inhibits the interaction, suggesting that PKC phosphorylation electrostatically interferes with calmodulin binding to basic arginine residues. Calmodulin binding was also inhibited by suramin. Our results suggest that EGFR-JM is essential for epidermal growth factor (EGF)-mediated calcium-calmodulin signalling and for signal integration between other signalling pathways.

  • 7.
    Aifa, Sami
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Miled, N
    Frikha, F
    Aniba, MR
    Svensson, Samuel
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Rebai, A
    Electrostatic interactions of peptides flanking the tyrosine kinase domain in the epidermal growth factor receptor provides a model for intracellular dimerization and autophosphorylation2006Ingår i: Proteins: Structure, Function, and Bioinformatics, ISSN 0887-3585, E-ISSN 1097-0134, Vol. 62, nr 4, s. 1036-1043Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The mechanism by which ligand-activated EGFR induces autophosphorylation via dimerization is not fully understood. Structural studies have revealed an extracellular loop mediated receptor dimerization. We have previously presented experimental data showing the involvement of a positive 13 amino acid peptide (R645-R657, P13+) from the intracellular juxtamembrane domain (JM) of EGFR important for intracellular dimerization and autophosphorylation. A model was presented that suggest that P13+ interacts with a negative peptide (D979-E991, P13-) positioned distal to the tyrosine kinase domain in the opposite EGFR monomer. The present work shows additional data strengthening this model. In fact, by analyzing protein sequences of 21 annotated ErbB proteins from 9 vertebrate genomes, we reveal the high conservation of peptides P13+ and P13- with regard to their sequence as well as their position relative to the tyrosine kinase (TK) domain. Moreover in silico structure modeling of these ErbB intracellular domains supports a general electrostatic P13+/P13- interaction, implying that the C-terminal of one receptor monomer is facing the TK domain of the other monomer in the receptor dimer and vice versa. This model provides new insights into the molecular mechanism of ErbB receptor activation and suggests a new strategy to pharmacologically interfering with ErbB receptor activity. © 2005 Wiley-Liss, Inc.

  • 8.
    Almroth, Gabriel
    et al.
    Linköpings universitet, Institutionen för medicin och vård, Njurmedicin. Linköpings universitet, Hälsouniversitetet.
    Ekermo, Bengt
    Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Transfusionsmedicin och klinisk immunologi. Linköpings universitet, Hälsouniversitetet.
    Månsson, A-S.
    Department of Clinical Virology, University Hospital of Malmö, Sweden.
    Svensson, Samuel
    Linköpings universitet, Institutionen för medicin och vård, Njurmedicin. Linköpings universitet, Hälsouniversitetet.
    Widell, A.
    Department of Clinical Virology, University Hospital of Malmö, Sweden.
    Detection and prevention of hepatitis C in dialysis patients and renal transplant recipients: A long-term follow up (1989–January 1997)2002Ingår i: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 251, nr 2, s. 119-128Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background. Hepatitis C is frequent problem in dialysis wards.

    Design.  A long time (1989–97) follow up of hepatitis C virus (HCV) infection in a Swedish nephrology unit was performed with anti-HCV screening, confirmatory antibody tests, viral RNA detection and molecular characterization. Case histories were reviewed with focus, onset of infection, liver morbidity and mortality.

    Results.  In October 1991, 10% (19 of 184) of the patients in the unit (haemodialysis-, peritoneal dialysis and transplanted patients) were verified or suspected HCV carriers, whilst the number at the end of 1996 was 8% (13 of 157). Most patients were infected before 1991 but only in one case from a known HCV-infected blood donor. No new HCV infections associated with haemodialysis occurred during the study period. A total of 13 of 24 viremic patients had HCV genotype 2b, a pattern suggesting nosocomial transmission. This was further supported by phylogenetic analysis of HCV viral isolates in seven. HCV viremia was also common in patients with an incomplete anti-HCV antibody pattern as 8 of the 12 indeterminant sera were HCV-RNA positive.

    Conclusions.  Awareness, prevention, identification of infected patients and donor testing limited transmission. Indeterminant recombinant immunoblot assays (RIBA)-results should be regarded with caution as a result of the relative immunodeficiency in uremic patients. Our data indicate nosocomial transmission in several patients.

  • 9.
    Anderson, Tony
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Filippini, Daniel
    Linköpings universitet, Tekniska högskolan. Linköpings universitet, Institutionen för fysik, kemi och biologi, Tillämpad Fysik.
    Suska, Anke
    Linköpings universitet, Institutionen för fysik, kemi och biologi. Linköpings universitet, Tekniska högskolan.
    Johansson, Therese
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Svensson, Samuel
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Lundström, Ingemar
    Linköpings universitet, Tekniska högskolan. Linköpings universitet, Institutionen för fysik, kemi och biologi, Tillämpad Fysik.
    Frog melanophores cultured on fluorescent microbeads: Biomimic-based biosensing2005Ingår i: Biosensors & bioelectronics, ISSN 0956-5663, E-ISSN 1873-4235, Vol. 21, nr 1, s. 111-120Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Melanophores are pigmented cells in lower vertebrates capable of quick color changes and thereby suitable as whole cell biosensors. In the frog dermis skin layer, the large and dark pigmented melanophore surrounds a core of other pigmented cells. Upon hormonal stimulation the black-brown pigment organelles will redistribute within the melanophore, and thereby cover or uncover the core, making complex color changes possible in the dermis. Previously, melanophores have only been cultured on flat surfaces. Here we mimic the three dimensional biological geometry in the frog dermis by culturing melanophores on fluorescent plastic microbeads. To demonstrate biosensing we use the hormones melatonin and α-melanocyte stimulating hormone (α-MSH) as lightening or darkening stimuli, respectively. Cellular responses were successfully demonstrated on single cell level by fluorescence microscopy, and in cell suspension by a fluorescence microplate reader and a previously demonstrated computer screen photo-assisted technique. The demonstrated principle is the first step towards "single well/multiple read-out" biosensor arrays based on suspensions of different selective-responding melanophores, each cultured on microbeads with distinctive spectral characteristics. By applying small amount of a clinical sample, or a candidate substance in early drug screening, to a single well containing combinations of melanophores on beads, multiple parameter read-outs will be possible. © 2004 Elsevier B.V. All rights reserved.

  • 10.
    Andersson, Tony
    et al.
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Nilsson Sköld, Helén
    Kristineberg Marine Research Station,Fiskebäckskil, Sweden.
    Svensson, Samuel
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Phosphoinositide 3-kinase is involved in Xenopus and Labrus melanophore aggregation2003Ingår i: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 15, nr 12, s. 1119-1127Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Melanophores are pigmented cells capable of quick colour changes through coordinated transport of their intracellular pigment granules. We demonstrate the involvement of phosphoinositide 3-kinase (PI3-K) in Xenopus and Labrus aggregation by the use of the PI3-K inhibitor, LY-294002. In Xenopus, wortmannin-insensitive PI3-K was found to be essential for the aggregation, mitogen-activated protein kinase (MAPK) activation and tyrosine phosphorylation of a 280-kDa protein, and for the maintenance of low cyclic adenosine 3′:5′-monophosphate (cAMP) during the aggregated state. Pre-aggregated cells disperse completely to LY-294002 at 50–100 μM, involving a transient elevation in cAMP due to adenylate cyclase (AC) stimulation or to inhibition of cyclic nucleotide phosphodiesterase (PDE). The inactive analogue LY-303511 did not induce dispersion at the same concentrations. PDE4 and/or PDE2 was found to be involved in melanosome aggregation. The similar kinetics of LY-294002 and various PDE inhibitors indicates that the elevation of cAMP might be due to inhibition of PDE. In Labrus melanophores, LY-294002 had a less dramatic effect, probably due to less dependence on PDE in regulation of cAMP levels. In Xenopus aggregation, we suggest that melatonin stimulation of the Mel1c receptor via Gβγ activates PI3-K that, directly or indirectly via MAPK, activates PDE.

  • 11.
    Andersson, Tony P. M.
    et al.
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Lundström, Ingemar
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Tillämpad Fysik. Linköpings universitet, Tekniska högskolan.
    Svensson, Samuel P. S.
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Myosin V is the rate-determinative step in Xenopus melanophore aggregationManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    In Xenopus melanophores, melatonin induce melanosome aggregation via activation of its receptor Mel1c, coupled to inhibitory G proteins, adenylate cyclase deactivation, cyclic adenosine 3':5'-monophosphate (cAMP) decrease, protein kinase A inhibition, protein phophatase 2A activation, and serine/threonine dephosphorylations. Myosin V is the motor protein responsible for transporting melanosomes along actin filaments. Myosin V has been demonstrated to be necessary for melanosome dispersion and to keep the dispersed state. We have previously shown that melatonin induce activation of phosphoinositide-3 kinase, mitogen-activated protein kinase and tyrosine phosphorylation of a 280-kDa protein. Here we characterize the kinetics of latrunculin A-induced aggregation, and show that latrunculin A aggregate melanophores with the same kinetics as melatonin. This indicates that the downstream mechanisms might be similar although their primary targets in the cells are totally different. We suggest that both drugs act by inhibiting myosin V, the rate-determinative step for melanosome aggregation. Our data suggest that dynein is not up regulated during aggregation, as previously suggested by others,

  • 12.
    Andersson, Tony
    et al.
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Svensson, Samuel
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Karlsson, Annika M.
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Regulation of melanosome movement by MAP kinase2003Ingår i: Pigment Cell Research, ISSN 1755-1471, E-ISSN 1755-148X, Vol. 16, nr 3, s. 215-221Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Our objectives were to further characterize the signaling pathways in melatonin-induced aggregation in Xenopus melanophores, specifically to investigate a possible role of mitogen-activated protein kinase (MAPK). By Western blotting we found that melatonin activates MAPK, which precedes melanosome aggregation measured in a microplate reader. Activation of MAPK, tyrosine phosphorylation of a previously described 280-kDa protein, and melanosome aggregation are sensitive to PD98059, a selective inhibitor of MAPK kinase. The MAPK activation is also decreased by the adenylate cyclase stimulant forskolin. In summary, we found that MAPK is activated during melatonin-induced melanosome aggregation. Activation was decreased by an inhibitor of MAPK kinase, and by forskolin. In addition to inhibition of cyclic adenosine 3′,5′-monophosphate (cAMP), reduction in protein kinase A activity (PKA), and activation of protein phosphatase 2A, we suggest that melatonin receptors activate the MAPK cascade and tyrosine phosphorylation of the 280-kDa protein. Although the cAMP/PKA signaling pathway is the most prominent, our data suggest that simultaneous activation of the MAPK cascade is of importance to obtain a completely aggregated state. This new regulatory mechanism of organelle transport by the MAPK cascade might be important in other eukaryotic cells.

  • 13. Avliakulov, NK
    et al.
    Lukes, J
    Kajava, AV
    Liedberg, B
    Lundström, I
    Svensson, Samuel
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Suramin blocks nucleotide triphosphate binding to ribosomal protein L3 from Trypanoplasma borreli2000Ingår i: European Journal of Biochemistry, ISSN 0014-2956, E-ISSN 1432-1033, Vol. 267, nr 6, s. 1723-1731Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Ribosomal protein L3 (L3) has been demonstrated to participate in formation of the peptidyltransferase center and is essential for its catalytic activity. In the present study we show that L3 is able to bind nucleotide triphosphates with high and specific affinity in vitro. L3 was serendipitously identified by screening of a genomic phage library from a primitive kinetoplastid flagellate Trypanoplasma borreli with the ATPase domain of the topoisomerase II gene as a probe. The cloned gene was overexpressed and purified as a his-tag fusion protein in E. coli. Radioligand binding experiments, using [?-35S]ATP, showed that L3 is able to bind ATP but also GTP and UTP with similar high affinity (IC50 50-100 nM), while it has no ATPase activity. Furthermore, we showed that L3 has more than 500-fold higher affinity for nucleotide triphosphates compared to the corresponding nucleotide monophosphates and diphosphates. Molecular genetic and biochemical analyses allowed us to localize the NTP binding domain of L3 to the N-terminal 296 residues. Suramin, a polysulfonated naphthylamine derivative of urea, known for its chemotherapeutic effects completely inhibited the binding of [?-35S]ATP at subclinical levels. Results obtained with surface plasmon resonance technology showed that suramin both forms weak multimolecular complexes with L3 and bind strongly to L3 in nearly stoichiometric amounts.

  • 14.
    Boman, Andrea
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Svensson, Samuel
    Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. CBD Solutions, Stockholm, Sweden.
    Boxer, Adam
    Memory and Aging Center, University of California, San Francisco, United States.
    Rojas, Julio C.
    Memory and Aging Center, University of California, San Francisco, United States.
    Seeley, William W.
    Memory and Aging Center, University of California, San Francisco, United States.
    Karydas, Anna
    Memory and Aging Center, University of California, San Francisco, United States.
    Miller, Bruce
    Memory and Aging Center, University of California, San Francisco, United States.
    Kågedal, Katarina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Svenningsson, Per
    Translational Neuropharmacology, Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden.
    Distinct lysosomal network protein profiles in parkinsonian syndrome cerebrospinal fluid2016Ingår i: Journal of Parkinson's Disease, ISSN 1877-7171, E-ISSN 1877-718X, Vol. 6, nr 2, s. 307-315Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Introduction: Clinical diagnosis of parkinsonian syndromes like Parkinson’s disease, corticobasal degeneration and progressive supranuclear palsy is hampered by overlapping symptomatology and lack of biomarkers for diagnosis, and definitive diagnosis is only possible post-mortem. Since impaired protein degradation plays an important role in many neurodegenerative disorders, we hypothesized that levels and profiles of lysosomal network proteins in cerebrospinal fluid could be changed in these parkinsonian syndromes.

    Methods: Cerebrospinal fluid samples were collected from Parkinson’s disease patients (n=18), clinically diagnosed 4-repeat tauopathy patients, corticobasal syndrome (n=6) and progressive supranuclear palsy (n=5), pathologically diagnosed progressive supranuclear palsy (n=8) and corticobasal degeneration patients (n=7). Each patient set was compared to its appropriate control group consisting of the same number of age and gender matched individuals. Lysosomal network protein levels were detected via Western blotting.

    Results: Lysosomal network proteins have markedly different cerebrospinal fluid protein levels and profiles in Parkinson’s disease, corticobasal degeneration and progressive supranuclear palsy. Lysosomal-associated membrane proteins 1 and 2 were significantly decreased in Parkinson´s disease; early endosomal antigen 1 was decreased and lysozyme increased in progressive supranuclear palsy; and lysosomal-associated membrane proteins 1 and 2, microtubule-associated protein 1 light chain 3 and lysozyme were increased in corticobasal degeneration.

    Conclusions: Lysosomal network proteins hold promise of being interesting novel candidates for biomarker studies and for elucidating disease mechanisms of Parkinson’s disease, corticobasal degeneration and progressive supranuclear palsy, but further validation studies will be needed to assess the specificity and the predictive value of these proteins in CSF.

  • 15.
    Borgegard, Tomas
    et al.
    AstraZeneca, Sweden .
    Gustavsson, Susanne
    AstraZeneca, Sweden .
    Nilsson, Charlotte
    AstraZeneca, Sweden .
    Parpal, Santiago
    AstraZeneca, Sweden .
    Klintenberg, Rebecka
    AstraZeneca, Sweden .
    Berg, Anna-Lena
    AstraZeneca, Sweden .
    Rosqvist, Susanne
    AstraZeneca, Sweden .
    Serneels, Lutgarde
    University of Louvain, Belgium University of Louvain, Belgium VIB Centre Biol Disease VIB, Belgium .
    Svensson, Samuel
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Olsson, Fredrik
    AstraZeneca, Sweden .
    Jin, Shaobo
    Karolinska Institute, Sweden .
    Yan, Hongmei
    AstraZeneca, Sweden .
    Wanngren, Johanna
    Karolinska Institute, Sweden .
    Jureus, Anders
    AstraZeneca, Sweden .
    Ridderstad-Wollberg, Anna
    AstraZeneca, Sweden .
    Wollberg, Patrik
    AstraZeneca, Sweden .
    Stockling, Kenneth
    AstraZeneca, Sweden .
    Karlstrom, Helena
    Karolinska Institute, Sweden .
    Malmberg, Asa
    AstraZeneca, Sweden .
    Lund, Johan
    AstraZeneca, Sweden .
    I. Arvidsson, Per
    AstraZeneca, Sweden Uppsala University, Sweden University of KwaZulu Natal, South Africa .
    De Strooper, Bart
    University of Louvain, Belgium University of Louvain, Belgium VIB Centre Biol Disease VIB, Belgium .
    Lendahl, Urban
    Karolinska Institute, Sweden .
    Lundkvist, Johan
    Alzacure Fdn, Sweden AstraZeneca, Sweden Karolinska Institute, Sweden .
    Alzheimers Disease: Presenilin 2-Sparing gamma-Secretase Inhibition Is a Tolerable A beta Peptide-Lowering Strategy2012Ingår i: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 32, nr 48, s. 17297-17305Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    gamma-Secretase inhibition represents a major therapeutic strategy for lowering amyloid beta (A beta) peptide production in Alzheimers disease (AD). Progress toward clinical use of gamma-secretase inhibitors has, however, been hampered due to mechanism-based adverse events, primarily related to impairment of Notch signaling. The gamma-secretase inhibitor MRK-560 represents an exception as it is largely tolerable in vivo despite displaying only a small selectivity between A beta production and Notch signaling in vitro. In exploring the molecular basis for the observed tolerability, we show that MRK-560 displays a strong preference for the presenilin 1(PS1) over PS2 subclass of gamma-secretases and is tolerable in wild-type mice but causes dose-dependent Notch-related side effect in PS2-deficient mice at drug exposure levels resulting in a substantial decrease in brain A beta levels. This demonstrates that PS2 plays an important role in mediating essential Notch signaling in several peripheral organs during pharmacological inhibition of PS1 and provide preclinical in vivo proof of concept for PS2-sparing inhibition as a novel, tolerable and efficacious gamma-secretase targeting strategy for AD.

  • 16.
    Eriksson, Therese
    et al.
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Svensson, Samuel
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Lundström, Ingemar
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Tillämpad Fysik. Linköpings universitet, Tekniska högskolan.
    Andersson, Rolf
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Role of ginsenosides and quercetin in anterograde transport of melanosomesManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Panax ginseng is a traditional herb that has been used in the Orient for several thousands of years as a tonic and restorative. Active components of ginseng include ginsenosides, polysaccharides, flavonoids, polyacetylenes, peptides, vitamins, phenols and enzymes, of which the ginsenosides are considered to be the major bioactive constituents. In spite of extensive use, the exact mechanisms of ginseng and its components are still unknown. In the present study we use melanophores from Xenopus laevis to investigate the effects of Panax ginseng extract G115, ginsenosides and the flavonoid quercetin on pigment organelle transport and signalling. Through coordinated transport of their black pigmented granules (melanosomes), melanophores are capable of fast colour changes. The movement is regulated by changes in cyclic adenosine 3’:5’-monophosphate (cAMP) concentration, where a high or low level induce anterograde (dispersion) or retrograde (aggregation) transport respectively, leaving a dark or light cell. Previously we have shown that Panax ginseng induces dispersion of melanosomes. Here, ginsenoside Rc and Rd and the flavonoid quercetin are shown to stimulate an anterograde transport of pigment organelles. When Rc or Rd and quercetin were combined, a significant synergistic increase in dispersion could be seen. Protein kinase C (PKC) inhibitor Myristoylated EGF-R Fragment (651-658) (M-EGF) decreased the anterograde movement stimulated by ginseng and ginsenoside Rc and Rd. We also demonstrate that ginseng, but not ginsenosides or quercetin, induce a concentration-dependent activation of 44/42-mitogen activated protein kinase (MAPK). PKC-inhibition did not affect the MAPK-activation, suggesting a role for PKC in the ginseng- and ginsenoside-induced anterograde transport but not in the activation of MAPK.

  • 17.
    Eriksson, Therese
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Svensson, Samuel
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Lundström, Ingemar
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Tillämpad Fysik. Linköpings universitet, Tekniska högskolan.
    Persson, Karin
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Andersson, Tony
    Landstinget i Kronoberg.
    Andersson, Rolf
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Panax ginseng induces anterograde transport of pigment organelles in Xenopus melanophores2008Ingår i: Journal of Ethnopharmacology, ISSN 0378-8741, E-ISSN 1872-7573, Vol. 119, nr 1, s. 17-23Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Melanophores from Xenopus laevis are pigmented cells, capable of quick colour changes through cyclic adenosine 3':5'-monophosphate (cAMP) coordinated transport of their intracellular pigment granules, melanosomes. In this study we use the melanophore cell line to evaluate the effects of Panax ginseng extract G115 on organelle transport. Absorbance readings of melanophore-coated microplates, Correlate-EIA direct cAMP enzyme immunoassay kit, and western blot were used to measure the melanosome movement and changes in intracellular signalling. We show that Panax ginseng induces a fast concentration-dependent anterograde transport of the melanosomes. No significant increase in the cAMP level was seen and pre-incubation of melanophores with the protein kinase C (PKC) inhibitor EGF-R Fragment 651-658 (M-EGF) only partly decreased the ginseng-induced dispersion. We also demonstrate that Panax ginseng, endothelin-3 (ET-3) and alpha-melanocyte stimulating hormone (MSH) stimulate an activation of mitogen activated protein kinase (MAPK). Pre-incubation with M-EGF decreased the MAPK activity induced by ET-3 and MSH, but again only marginally affected the response of Panax ginseng. Thus, in melanophores we suggest that Panax ginseng stimulates an anterograde transport of pigment organelles via a non-cAMP and mainly PKC-independent pathway.

  • 18. Filippini, D
    et al.
    Svensson, Samuel
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Lundström, I
    Computer screen as a programmable light source for visible absorption characterization of (bio)chemical assays2003Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Visible absorption features suitable for color recognition and micro-plate reading of a standard bioassay are performed by the combination of a computer screen used as a programmable light source and a web camera as detector. The method provides in this way a highly available platform for 'home tests' or 'self-tests', where the requirement is to monitor well defined assays and the use of economical instrumentation is advantageous.

  • 19.
    Filippini, Daniel
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Tillämpad Fysik. Linköpings universitet, Tekniska högskolan.
    Andersson, Tony
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Svensson, Samuel
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Lundström, Ingemar
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Tillämpad Fysik. Linköpings universitet, Hälsouniversitetet.
    Microplate based biosensing with a computer screen aided technique2003Ingår i: Biosensors & bioelectronics, ISSN 0956-5663, E-ISSN 1873-4235, Vol. 19, nr 1, s. 35-41Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Melanophores, dark pigment cells from the frog Xenopus laevis, have the ability to change light absorbance upon stimulation by different biological agents. Hormone exposure (e.g. melatonin or α-melanocyte stimulating hormone) has been used here as a reversible stimulus to test a new compact microplate reading platform. As an application, the detection of the asthma drug formoterol in blood plasma samples is demonstrated. The present system utilizes a computer screen as a (programmable) large area light source, and a standard web camera as recording media enabling even kinetic microplate reading with a versatile and broadly available platform, which suffices to evaluate numerous bioassays. Especially in the context of point of care testing or self testing applications these possibilities become advantageous compared with highly dedicated comparatively expensive commercial systems.

  • 20.
    Grenegård, Magnus
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Whiss, Per A
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Svensson, Samuel
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    The novel nitric oxide-donor GEA 3175 and adenosine inhibit intracellular responses in thrombin-activated platelets1997Ingår i: FEBS special meeting: Cell Signalling Mechanisms, From Membrane to Nucleus,1997, 1997Konferensbidrag (Övrigt vetenskapligt)
  • 21.
    Hammarström, Per
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biokemi. Linköpings universitet, Tekniska högskolan.
    Ali Malik, Muhammad
    Linköpings universitet, Institutionen för fysik, kemi och biologi. Linköpings universitet, Tekniska högskolan.
    Mishra, Rajesh
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biokemi. Linköpings universitet, Tekniska högskolan.
    Svensson, Samuel
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Tengvall, Pentti
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Tillämpad Fysik. Linköpings universitet, Tekniska högskolan.
    Lundström, Ingemar
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Tillämpad Fysik. Linköpings universitet, Tekniska högskolan.
    A catalytic surface for amyloid fibril formation2008Ingår i: Journal of Physics, Conference Series, ISSN 1742-6588, E-ISSN 1742-6596, Vol. 100Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A hydrophobic surface incubated in a solution of protein molecules (insulin monomers) was made into a catalytic surface for amyloid fibril formation by repeatedly incubate, rinse and dry the surface. The present contribution describes how this unexpected transformation occurred and its relation to rapid fibrillation of insulin solutions in contact with the surface. A tentative model of the properties of the catalytic surface is given, corroborated by ellipsometric measurements of the thickness of the organic layer on the surface and by atomic force microscopy. The surfaces used were spontaneously oxidized silicon made hydrophobic through treatment in dichlorodimethylsilane.

  • 22.
    Johansson, Fredrik
    et al.
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Andersson, Rolf
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Lindström, Eva
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Svensson, Samuel
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    An indomethacin-sensitive contraction induced by β-antagonists in guinea pig airways2004Ingår i: Canadian Journal of Physiology and Pharmacology, ISSN 0008-4212, E-ISSN 1205-7541, Vol. 82, nr 6, s. 393-401Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    β-adrenergic receptor (β-AR) antagonists have been associated with increased airway reactivity in asthmatics and potentiation of contractile stimuli in animal models. In the present study, using an in vitro model of tracheal preparations from guinea pigs, we show that the β-AR antagonists propranolol and pindolol induce a smooth muscle contraction. A prerequisite for this contraction is that the airway preparations have been pre-treated with an β-AR agonist. Our data show that the contractile effect of β-AR antagonists is not a simple consequence of reversing the agonist-induced relaxation. Furthermore, the effect seems to be mediated through interaction with β2-ARs since the response is stereo-selective, and the selective β1-AR receptor antagonist atenolol did not induce any contractile response. SQ 29,546, a thromboxane A2 antagonist; MK 886, a lipoxygenase inhibitor; and indomethacin, a cyclooxygenase inhibitor significantly inhibited the contractions of the tracheal preparations induced with propranolol or pindolol. We put forward the hypothesis that the contractile effect of the β-AR antagonist is a consequence of their inverse agonist activity, which is only evident when the receptor population have a higher basal activity. Our results indicate a novel additional explanation for the known side effect, bronchoconstriction, of β-AR antagonist.Key words: beta antagonist, guinea pig trachea, propranolol, formoterol, pindolol, indomethacin.

  • 23.
    Johansson, Fredrik
    et al.
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Andersson, Tony P. M.
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Lundström, Ingemar
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Tillämpad Fysik. Linköpings universitet, Hälsouniversitetet.
    Svensson, Samuel P. S.
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Is effect of (S;S)-formoterol due to contamination of (R;R)-formoterol?Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Formoterol is a long acting selective ß2-adrenoceptor (ß2-AR) agonist of the so-called third generation of ß-adrenoceptor agonists. lt also has an onset action comparable to most short acting ß2-AR agonists. Formoterol has two chiral centres making four enantiomers possible. In this study we have examined (R;R)- and (S;S)-formoterol relaxing effect on guinea pig tracheal ring preparations, affinity to human ß2-AR in transfected COS-7 cells and the ability to influence pigment movement in frog melanophores with stable expression of human ß2AR. We also compared single concentration curves versus cumulative concentration curves on guinea pig tracheal preparations. In all three systems the (R;R)-formoterol is the most potent ß2AR agonist compered to (S;S)-formoterol with eudismic ratios ranging from 11 to 75. We also measure and theoretically calculated the effect of (S;S)-formoterol. VVhen the contamination of (R;R)-formoterol was subtracted the (S;S)-formoterol had effect, although approximately 72 times less then (R;R)-formoterol. We conclude that (R;R)-formoterol is the most potent ß2-AR agonist in three different systems and that (S;S)-formoterol posses an ß2-AR effect. We also show that cumulative concentration curves have higher EC50 values compered to single concentration curves and that this might be a consequence of recaptor desensitisation.

  • 24.
    Karlsson, Annika M.
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Bjuhr, Katarina
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Testorf, Martin
    Linköpings universitet, Institutionen för medicinsk teknik, Fysiologisk mätteknik. Linköpings universitet, Tekniska högskolan.
    Öberg, Åke
    Linköpings universitet, Institutionen för medicinsk teknik, Fysiologisk mätteknik. Linköpings universitet, Tekniska högskolan.
    Lerner, Ethan
    Bunsen Rush Laboratories, Dallas, TX, USA.
    Lundström, Ingemar
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Tillämpad Fysik. Linköpings universitet, Tekniska högskolan.
    Svensson, Samuel P.S.
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Biosensing of opioids using frog melanophores2002Ingår i: Biosensors and Bioelectronics, ISSN 0956-5663, Vol. 17, nr 4, s. 331-335Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Spectacular color changes of fishes, frogs and other lower vertebrates are due to the motile activities of specialized pigment containing cells. Pigment cells are interesting for biosensing purposes since they provide an easily monitored physiological phenomenon. Melanophores, containing dark brown melanin pigment granules, constitute an important class of chromatophores. Their melanin-filled pigment granules may be stimulated to undergo rapid dispersion throughout the melanophores (cells appear dark), or aggregation to the center of the melanophores (cells appear light). This simple physiological response can easily be measured in a photometer. Selected G protein coupled receptors can be functionally expressed in cultured frog melanophores. Here, we demonstrate the use of recombinant frog melanophores as a biosensor for the detection of opioids. Melanophores were transfected with the human opioid receptor 3 and used for opiate detection. The response to the opioid receptor agonist morphine and a synthetic opioid peptide was analyzed by absorbance readings in an aggregation assay. It was shown that both agonists caused aggregation of pigment granules in the melanophores, and the cells appeared lighter. The pharmacology of the expressed receptors was very similar to its mammalian counterpart, as evidenced by competitive inhibition by increasing concentrations of the opioid receptor inhibitor naloxone. Transfection of melanophores with selected receptors enables the creation of numerous melanophore biosensors, which respond selectively to certain substances. The melanophore biosensor has potential use for measurement of substances in body fluids such as saliva, blood plasma and urine.

  • 25.
    Karlsson, Annika M.
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Lerner, Michael R.
    Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
    Unett, David
    Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
    Lundström, Ingemar
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Tillämpad Fysik. Linköpings universitet, Tekniska högskolan.
    Svensson, Samuel P.S.
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Melatonin-induced organelle movement in melanophores is coupled to tyrosine phosphorylation of a high molecularweight protein2000Ingår i: Cellular signalling, ISSN 0898-6568, Vol. 12, nr 7, s. 469-474Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Melanophores, brown to black pigment cells from, for example, Xenopus laevis, contain mobile melanin filled organelles, and are well suited for studies on organelle movement. The intracellular regulation of the movement seems to be controlled by serine and threonine phosphorylations and dephosphorylations. Melatonin induces aggregation of the melanosomes to the cell centre through a Gi/o-protein-coupled receptor, Mel1c, which leads to an inhibition of PKA and a stimulation of PP2A. However, this study shows that the melatonin-induced aggregation of melanosomes is also accompanied by tyrosine phosphorylation of a protein with a molecular weight of 280 kDa. Cells pre-incubated with genistein, an inhibitor of tyrosine phosphorylations, showed inhibited melanosome movement after melatonin stimulation, and a lower degree of tyrosine phosphorylation of the 280 kDa protein. The adenylyl cyclase activator forskolin, and the Gi/o protein inhibitor pertussis toxin, also inhibited tyrosine phosphorylation of the 280 kDa protein. The results indicate that melatonin stimulation generates tyrosine phosphorylation of a high molecular weight protein, an event that seems to be essential for melanosome aggregation.

  • 26. Kjellgren, K.I.
    et al.
    Svensson, Samuel
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi.
    Ahlner, Johan
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi.
    Saljo, R.
    Antihypertensive treatment and patient autonomy - The follow-up appointment as a resource for care2000Ingår i: Patient Education and Counseling, ISSN 0738-3991, E-ISSN 1873-5134, Vol. 40, nr 1, s. 39-49Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Since hypertension is a chronic condition which generally requires long-term commitment to pharmacological therapy as well as alterations of patient lifestyle, the patient-physician communication in the clinical setting is an important determinant of the quality of care and health outcome. The aim of the present study was to explore the structure and content of the communication between the patient and the physician, and the process of decision-making at a routine follow-up appointment for hypertension. The study was based on 51 audio-recordings of authentic consultations. Most patients had a passive role in the consultations, and initiated few topics of conversation. The few topics that the patients initiated were usually not about hypertension. Patients' questions about medication mainly referred to unwanted effects of the drugs. Little time was invested in discussing risks related to hypertension. A collaborative shared decision-making was seldom observed in the consultations. Copyright (C) 2000 Elsevier Science Ireland Ltd.

  • 27.
    Lundström, Ingemar
    et al.
    Linköpings universitet, Tekniska högskolan. Linköpings universitet, Institutionen för fysik, kemi och biologi, Tillämpad Fysik.
    Svensson, Samuel
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Natural nanosystems2002Ingår i: Current applied physics, ISSN 1567-1739, E-ISSN 1878-1675, Vol. 2, nr 1, s. 17-21Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A short review of our work on pigment containing cells as biosensors is given. It is pointed out that they combine several natural nanosystems, namely membrane bound receptors and their biochemical machinery, and the tubulin/actin network inside the cells for transport of submicron-sized pigment particles driven by molecular motors of 10-100 nm size.

  • 28.
    Monstein, H.-J.
    et al.
    Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Nilsson, Isabelle
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Klinisk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Ellnebo-Svedlund, Katarina
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Klinisk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Svensson, S.P.S.
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Cloning and characterization of 5'-end alternatively spliced human cholecystokinin-B receptor mRNAs1998Ingår i: Receptors and Channels, ISSN 1060-6823, E-ISSN 1607-856X, Vol. 6, nr 3, s. 165-177Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We report here the cloning and characterization of a 5'-end alternatively spliced human cholecystokinin-B (CCK-B) receptor mRNA. The 5'-end of this CCK-B receptor transcript (termed CCK-BRtx) consisted of exon Ia, present in the ordinary full-length CCK-B receptor mRNA (CCK-BRwt), and exon Ib, present in a previously described 5'-end alternatively spliced CCK-B receptor mRNA (CCK-BRt). A short open reading frame preceded the AUG translation initiation codon of the CCK-BRtx. Transfection of COS-7 cells with the CCK-BRtx or CCK-BRt cDNAs did not lead to the appearance of peptidergic and non-peptidergic binding sites. Cell free in vitro translation yielded proteins of approximately 44 kDa (CCK-B receptor) and 40 kDa (CCK-BRt receptor) whereas no 40 kDa product was detected from the cloned CCK-BRtx cDNA. Instead, a protein product of approximately 9 kDa was visualized, the size corresponding to the predicted protein encoded by the short open reading frame. The alternatively spliced CCK-B receptor transcripts were concomitantly expressed with the ordinary full-length CCK-B receptor mRNA in the brain, pancreas, and stomach. The possibility that such transcripts are translated in vivo into truncated CCK-B receptors is discussed.

  • 29.
    Nilsson, Harriet M.
    et al.
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Holmgren Peterson, Kajsa
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Svensson, Samuel P. S.
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Sundqvist, Tommy
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    HgCl2-sensitive aquaporins are not involved in melanosome aggregation in Xenopus laevis melanophoresManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Melanophores are cells specialized for transport of pigment-filled organelles called melanosomes. Melanosomes are aggregated in the center of a melanophore or dispersed throughout the cytoplasm by motor proteins moving along the actin and microtubule cytoskeleton. In angelfish (Pterophyllum scalare), aggregation of melanosomes (as compared to dispersion) increases the height of the central part of melanophores by 300%. Our objective was to detennine whether such a height increase also occurs in frog (Xenopus laevis) melanophores. In analogy with theories explaining the leading edge of migrating cells, we investigated the possibility that elevation of the melanophore plasma membrane is due to local swelling caused by influx of water through HgCl2-sensitive aquaporins and subsequent polymerization of actin. Confocal microscopy revealed a 30% increase in height in X. laevis melanophores during melatonin-induced aggregation. This was not due to actin polymerization, because it also occurred when aggregation was induced by the polymerization inhibitor latrunculin B. The nitric oxide (NO) synthase inhibitor L-NAME induced dispersion and lowered the plasma membrane, which suggests that NO is involved in the upward movement. Furthermore, neither dispersion nor aggregation was affected by inhibition of water flux through HgCl2 sensitive aquaporins. Together, these observations imply that melanosomes in X. laevis melanophores are driven upwards during aggregation by a mechanism other than actin polymerization, possibly involving microtubules, intermediate filaments, or a motor protein that may be regulated by NO. Furthermore, influx of water through HgCl2-sensitive aquaporins is probably not necessary for aggregation-induced elevation of the cell membrane, because both aggregation and dispersion can occur in the presence of HgCl2.

  • 30.
    Nilsson, Harriet M.
    et al.
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Karlsson, Annika M.
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Loitto, Vesa-Matti
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Svensson, Samuel P.S.
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Sundqvist, Tommy
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Nitric oxide modulates intracellular translocation of pigment organelles in Xenopus laevis melanophores2000Ingår i: Cell Motility and the Cytoskeleton, ISSN 0886-1544, E-ISSN 1097-0169, Vol. 47, nr 3, s. 209-218Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Pigment organelles in Xenopus laevis melanophores are used by the animal to change skin color, and they provide a good model for studying intracellular organelle transport. Movement of organelles and vesicles along the cytoskeleton is essential for many processes, such as axonal transport, endocytosis, and intercompartmental trafficking. Nitric oxide (NO) is a signaling molecule that plays a role in, among other things, relaxation of blood vessels, sperm motility, and polymerization of actin. Our study focused on the effect NO exerts on cytoskeleton-mediated transport, which has previously received little attention. We found that an inhibitor of NO synthesis, N-nitro-L-arginine methyl ester (L-NAME), reduced the melatonin-induced aggregation of the pigment organelles, melanosomes. Preaggregated melanosomes dispersed after treatment with L-NAME but not after exposure to the inactive stereoisomer (D-NAME) or the substrate for NO synthesis (L-arginine). Signal transduction by NO can be mediated through the activation of soluble guanylate cyclase (sGC), which leads to increased production of cGMP and activation of cGMP-dependent kinases (PKG). We found that both the sGC inhibitor 1H-(1,2,4) oxadiazolo(4,3-a)quinoxalin-1-one (ODQ) and the cGMP analogue 8-bromoguanosine 3′:5′-cyclic monophosphate (8-Br-cGMP) reduced melanosome aggregation, whereas the PKG inhibitor KT582 did not. Our results demonstrate that melanosome aggregation depends on synthesis of NO, and NO deprivation causes dispersion. It seems, thus, as if NO and cGMP are essential and can regulate melanosome translocation.

  • 31.
    Nilsson, Harriet M.
    et al.
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Svensson, Samuel
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Sundqvist, Tommy
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    L-NAME-induced dispersion of melanosomes in melanophores activates PKC, MEK and ERK12001Ingår i: Pigment Cell Research, ISSN 1755-1471, E-ISSN 1755-148X, Vol. 14, nr 6, s. 450-455Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Melanosome movement represents a good model of cytoskeleton-mediated transport of organelles in eukaryotic cells. We recently observed that inhibiting nitric oxide synthase (NOS) with Nω-nitro-l-arginine methyl ester (l-NAME) induced dispersion in melanophores pre-aggregated with melatonin. Activation of cyclic adenosine 3′,5′-monophosphate (cAMP)-dependent protein kinase (PKA) or calcium-dependent protein kinase (PKC) is known to cause dispersion. Also, PKC and NO have been shown to regulate the mitogen/extracellular signal-regulated kinase (MEK)-ERK pathway. Accordingly, our objective was to further characterize the signaling pathway of l-NAME-induced dispersion. We found that the dispersion was decreased by staurosporine and PD98059, which respectively inhibit PKC and MEK, but not by the PKA inhibitor H89. Furthermore, Western blotting revealed that ERK1 kinase was phosphorylated in l-NAME-dispersed melanophores. l-NAME also caused dispersion in latrunculin-B-treated cells, suggesting that this effect is not due to inhibition of the melatonin signaling pathway. Summarizing, we observed that PKC and MEK inhibitors decreased the l-NAME-induced dispersion, which caused phosphorylation of ERK1. Our results also suggest that NO is a negative regulator of phosphorylations that leads to organelle transport.

  • 32.
    Nilsson, Isabelle
    et al.
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Monstein, Hans-Jurg
    Östergötlands Läns Landsting, LMÖ - Laboratoriemedicin i Östergötland.
    Lindström, Erik
    Department of Pharmacology, Institute of Physiological Sciences, University of Lund, Lund, Sweden.
    Håkanson, Rolf
    Department of Pharmacology, Institute of Physiological Sciences, University of Lund, Lund, Sweden.
    Svensson, Samuel
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Pharmacological analysis of CCK2 receptor ligands using COS-7 and SK-N-MC cells, expressing the human CCK2 receptor2002Ingår i: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 103, nr 1, s. 29-37Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A series of CCK2 receptor ligands were analysed with respect to their interaction with binding sites in the membranes of COS-7 cells and SK-N-MC cells transiently expressing the human CCK2 receptor (short isoform). The ligands were YF476, YM022, AG041R, L-740,093, JB93182, PD134308, and PD136450. Their binding was analysed by radioligand competition using [3H]L-365,260 as the labelled ligand. Saturation binding analysis indicated that [3H]L-365,260 interacted with a single class of binding sites. In competition binding experiments using COS-7-cell membranes, all seven ligands were incubated together with 2 nM [3H]L-365,260. The data for four of the compounds fitted a one-site model (pKi values: YM022: 9.2±0.02; YF476: 9.6±0.04; L-740,093: 9.2±0.01; and AG041R: 8.3±0.06), while the data for the three others fitted a two-site model (pKi values: JB93182: 8.8±0.04 and 6.0±0.15; PD134308: 9.0±0.04 and 6.1±0.15; and PD136450: 9.0±0.02 and 5.4±0.41). SK-N-MC cell membranes and 2 nM [3H]L-365,260 were incubated together with YM022, YF476, JB93182, and PD134308. The data for YM022 and YF476 fitted a one-site model (pKi values: YM022: 9.3±0.06; YF476: 9.4±0.02), while the data for JB93182 and PD134308 fitted a two-site model (pKi values: JB93182: 8.7±0.06 and 6.2±0.06; PD134308: 9.1±0.06 and 7.0±0.17). Competition binding experiments in the presence of the GTP-analogue guanylylimidodiphosphate, using either of the two cell types, produced similar binding data for PD134308 and JB93182 as in the absence of GTP-analogue. The human receptor seems to exist in a low and/or high affinity state. The shift from low to high affinity does not seem to reflect the degree of G protein coupling.

  • 33.
    Nilsson, Isabelle
    et al.
    Östergötlands Läns Landsting, LMÖ - Laboratoriemedicin i Östergötland. Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Svensson, Samuel
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Monstein, Hans-Jurg
    Östergötlands Läns Landsting, LMÖ - Laboratoriemedicin i Östergötland. Linköpings universitet, Institutionen för biomedicin och kirurgi. Linköpings universitet, Hälsouniversitetet.
    Molecular cloning of a putative Ciona intestinalis cionin receptor, a new member of the CCK/gastrin receptor family2003Ingår i: Gene, ISSN 0378-1119, E-ISSN 1879-0038, Vol. 323, nr 1-2, s. 79-88Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cionin, a peptide showing similarities with cholecystokinin and gastrin has been shown to be expressed in the gut and neural ganglion of the protochordate Ciona intestinalis. The present report describes the cloning of a putative cionin receptor (CioR), a new member of the CCK/gastrin family from the gastrointestinal tract of C. intestinalis. mRNA from the stomach of C. intestinalis was isolated using a modified RNA extraction procedure and, subsequently, reverse-transcribed into single-stranded cDNA by means of rapid amplification of 5′- and 3′-cDNA ends (RACE-PCR), followed by full-length PCR amplification. The cloned full-length PCR amplicons contained a short upstream open-reading frame (uORF) coding for a putative 16 amino acid long peptide, followed by a long open reading frame encoding a 526 amino acid putative CioR protein. At the amino acid level, the putative CioR protein shared 35–40% homology with cloned mammalian, chicken, and Xenopus laevis CCK receptors. Phylogenetic analysis revealed that the chicken and X. laevis CCK receptors are orthologues of the mammalian CCK2 receptors whereas CioR protein forms a clade with vertebrate cholecystokinin receptors. Moreover, we found that the CioR cDNA and deduced amino acid sequences were found to correspond to the annotated CCK/gastrin-like receptor gene on Scaffold 117 (C. intestinalis draft genome project, Joint Genome Institute database; http://www.jgi.doe.gov).

  • 34.
    Nilsson, Isabelle
    et al.
    Östergötlands Läns Landsting, LMÖ - Laboratoriemedicin i Östergötland. Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Svensson, Samuel
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Monstein, Hans-Jürg
    Östergötlands Läns Landsting, LMÖ - Laboratoriemedicin i Östergötland. Linköpings universitet, Institutionen för biomedicin och kirurgi. Linköpings universitet, Hälsouniversitetet.
    Molecular cloning of an unusual bicistronic cholecystokinin receptor mRNA expressed in chicken brain: a structural and functional expression study2003Ingår i: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 114, nr 1, s. 37-43Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    This report describes the molecular cloning and pharmacological characterization of a transiently expressed chicken brain cholecystokinin receptor (CCK-CHR) in COS-7 cells. A polymerase chain reaction (PCR)-based cloning strategy was applied using: (1) an initial PCR with deoxyinosine-containing primers designed to target conserved regions in CCK receptors, followed by (2) rapid amplification of cDNA ends (RACE), and (3) full-length PCR of the CCK-CHR cDNA. The full-length cloned bicistronic CCK-CHR cDNA contained a short upstream open reading frame (uORF) coding for a putative six-amino-acid-long peptide of unknown function, followed by a long open reading frame (lORF) encoding the 436-amino-acid-long CCK-CHR receptor protein. At the amino acid level, the CCK-CHR shared ∼50% homology with mammalian and Xenopus laevis CCK receptors. The pharmacological profile of CCK-CHR resembled that of CCK-B receptors using agonists (CCK-8, CCK-4, gastrin-17), whereas CCK-CHR showed higher affinity for the CCK-A receptor antagonist, devazepide, than for the CCK-B receptor antagonist, l-365,260. To the best of our knowledge, this is the first description and functional expression study of a cloned chicken CCK receptor cDNA.

  • 35.
    Nilsson, Ulrika K.
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Andersson, Rolf G. G.
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Ekeroth, Johan
    Linköpings universitet, Institutionen för fysik, kemi och biologi.
    Hallin, Elisabeth C.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Konradsson, Peter
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Organisk Kemi. Linköpings universitet, Tekniska högskolan.
    Lindberg, Jan
    Linköpings universitet, Institutionen för fysik, kemi och biologi.
    Svensson, Samuel P.S.
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Lack of stereospecificity in lysophosphatidic acid enantiomerinduced calcium mobilization in human erythroleukemia cells2003Ingår i: Lipids, ISSN 0024-4201, Vol. 38, nr 10, s. 1057-1064Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Lysophosphatidic acid (LPA) is a lipid mediator that, among several other cellular responses, can stimulate cells to mobilize calcium (Ca2+). LPA is known to activate at least three different subtypes of G protein-coupled receptors. These receptors can then stimulate different kinds of G proteins. In the present study, LPA and LPA analogs were synthesized from (R)- and (S)-glycidol and used to characterize the ability to stimulate Ca2+ mobilization. The cytosolic Ca2+ concentration ([Ca2+]i) was measured in fura-2-acetoxymethylester-loaded human erythroleukemia (HEL) cells. Furthermore, a reverse transcriptase polymerase chain reaction was used to characterize LPA receptor subtypes expressed in HEL cells. The results show that HEL cells mainly express LPA1 and LPA2, although LPA3 might possibly be expressed as well. Moreover, LPA and its analogs concentration-dependently increased [Ca2+]i in HEL cells. The response involved both influx of extracellular Ca2+ and release of Ca2+ from intracellular stores. This is the first time the unnatural (S)-enantiomer of LPA, (S)-3-O-oleoyl-1-O-phosphoryl-glycerol, has been synthesized and studied according to its ability to activate cells. The results indicate that this group of receptors does not discriminate between (R)- and (S)-enantiomers of LPA and its analogs. When comparing ether analogs having different hydrocarbon chain lengths, the tetradecyl analog (14 carbons) was found to be the most effective in increasing [Ca2+]i. Pertussis toxin treatment of the HEL cells resulted in an even more efficient Ca2+ mobilization stimulated by LPA and its analogs. Furthermore, at repeated incubation with the same ligand no further increase in [Ca2+]i was obtained. When combining LPA with the ether analogs no suppression of the new Ca2+ signal occurred. All these findings may be of significance in the process of searching for specific agonists and antagonists of the LPA receptor subtypes.

  • 36.
    Nilsson, Ulrika K.
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Grenegård, Magnus
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Berg, Göran
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Obstetrik och gynekologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Kvinnokliniken i Linköping.
    Svensson, Samuel P.S.
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Different proliferative responses of Gi/o-protein-coupled receptors in human myometrial smooth muscle cells: a possible role of calcium1998Ingår i: Journal of Molecular Neuroscience, ISSN 0895-8696, Vol. 11, nr 1, s. 11-21Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The majority of studies investigating the proliferative effect of Gi/o-protein-coupled receptor agonists are performed in recombinant receptor systems or cell lines. In these systems the relative stoichiometry of receptors compared to other cell components might be changed, which may lead to anomalies in cellular responses in contrast to natural occurring systems. In the present study, we have used primary cultures of smooth muscle cells (SMCs) isolated from human myometrium to characterize the proliferative effects of agonists binding to two different G protein-coupled receptors. Treatment of quiescent SMCs with lysophosphatidic acid (LPA) and noradrenaline resulted in significant increases in [3H]thymidine incorporation. However, LPA was almost four times more effective than noradrenaline in this respect. The proliferative effects of the agonists could be completely blocked by pertussis toxin, indicating that the response are mediated through Gi/o-proteins. The selective α2-adrenergic receptor (α2-AR) antagonist yohimbine dose-dependently reduced the effect of noradrenaline suggesting that the proliferative response was mediated through α2-ARs. The proliferative effects induced by LPA and noradrenaline was markedly reduced in SMCs treated with the tyrosine kinase inhibitor genistein and the cAMP elevating compound forskolin. However, LPA but not noradrenaline induced rapid rises in the cytosolic free Ca2+ concentration [Ca2+]i. The ability to increase Ca2+ might be one explanation why LPA produce a more pronounced proliferative response than noradrenaline in primary cultures of human myometrial SMCs.

  • 37.
    Nilsson, Ulrika K.
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Grenegård, Magnus
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Svensson, Samuel P.S.
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Synergistic activation of human platelets by adrenaline and lysophosphatidic acid2002Ingår i: Haematologica, ISSN 0390-6078, Vol. 87, nr 7, s. 730-739Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND AND OBJECTIVES: Platelet reactivity is regulated by various important bioactive and physiologic substances. The objective of this study was to characterize lysophosphatidic acid (LPA)-triggered responses in human platelets. In addition, the effect of LPA was compared with that of other activators and possible synergistic interactions were evaluated.

    DESIGN AND METHODS: LPA-triggered cytosolic Ca(2+) responses were measured using fura-2-loaded platelets in a spectrofluorometer. Furthermore, platelet aggregation and secretion were analyzed in a lumi-aggregometer and protein tyrosine phosphorylation was detected with the Western blot technique.

    RESULTS: LPA dose-dependently increased cytosolic Ca(2+) concentration ([Ca(2+)](i)) in platelets. This response involved both influx of extracellular Ca(2+) and release of Ca(2+) from intracellular stores. However, in comparison with other platelet agonists, i.e. thrombin and adenosine 5'-diphosphate (ADP), LPA was a very weak Ca(2+)-elevating agent. Furthermore, we observed that the LPA-induced rise in [Ca(2+)](i) was markedly suppressed by cyclic nucleotide-elevating agents. In functional studies, LPA failed to stimulate platelet aggregation and secretion. However, in combination with adrenaline, another weak platelet agonist, LPA could induce an irreversible and complete aggregatory response. There was an individual variation in aggregatory response and tyrosine phosphorylation when LPA and adrenaline were combined. These agents induced a powerful response on platelets from some individuals, but had a weak or no effect on others.

    INTERPRETATION AND CONCLUSIONS: The present study shows, for the first time, that isolated platelets from some healthy blood donors respond synergistically to a combination of LPA and adrenaline. Platelet activation is a key step in distinguishing normal hemostasis from pathologic hemostasis. Increased knowledge about this mechanism might help to predict individual responses and provide new insights into molecular mechanisms responsible for pathologic thrombosis.

  • 38.
    Nilsson, Ulrika K.
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Svensson, Samuel P.S.
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Inhibition of Ca2 +/calmodulin-dependent protein kinase or epidermal growth factor receptor tyrosine kinase abolishes lysophosphatidic acid-mediated DNA-synthesis in human myometrial smooth muscle cells2003Ingår i: Cell Biology International, ISSN 1065-6995, Vol. 27, nr 4, s. 341-347Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Human myometrial smooth muscle cells (SMCs) were used to evaluate the proliferative activity of lysophosphatidic acid (LPA). This study specifically focuses on the role of Ca2+/calmodulin-dependent protein (CaM) kinase and epidermal growth factor (EGF) receptor tyrosine kinase. Myometrial SMCs were cultured from biopsies taken at Cesarean sections. The expression of LPA receptors was determined by reverse transcriptase polymerase chain reaction (RT-PCR), and DNA-synthesis was measured by [3H]thymidine incorporation. LPA1, LPA2, and LPA3receptor subtypes were detected in the SMCs using RT-PCR. KN-62, an inhibitor of CaM kinase, and Tyrphostin AG 1478, an inhibitor of EGF receptor tyrosine kinase, dose-dependently decreased LPA-stimulated [3H]thymidine incorporation. Furthermore, BB-3103, an inhibitor of matrix metalloproteinases (MMPs), also reduced DNA-synthesis induced by LPA in these cells. The results show, for the first time, that human myometrial SMCs express all three known LPA receptor subtypes. Growth stimulatory effects of LPA on myometrial SMCs seems to be mediated by several pathways, where transactivation of EGF receptors through MMPs appears to be of importance. Furthermore, CaM kinase activity may be critical for LPA signaling since inhibition of CaM kinase totally abolish the proliferative effect of LPA.

  • 39. Porter, AC
    et al.
    Svensson, Samuel
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Stamer, WD
    Bahl, JJ
    Richman, JG
    Reagan, J
    Alpha-2adrenergic receptors stimulate actin organization in developing fetal rat cardiac myocytes2003Ingår i: Life Sciences, ISSN 0024-3205, E-ISSN 1879-0631, Vol. 72, s. 1455-1466Artikel i tidskrift (Refereegranskat)
  • 40.
    Powell, Wendy
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Green, Henrik
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Svensson, Samuel
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    A new method for screening the melanin binding ability of different antineoplastic agents.2001Ingår i: Pigment cell research,2001, 2001, s. 397-397Konferensbidrag (Refereegranskat)
  • 41.
    Strömberg, H
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Cellbiologi.
    Svensson, Samuel
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Hermansson, O
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Cellbiologi.
    Distribution of CREB-binding protein immunreactivity in the adult rat brain1999Ingår i: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 818, s. 510-514Artikel i tidskrift (Refereegranskat)
  • 42.
    Strömberg, H
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Cellbiologi.
    Svensson, Samuel
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Hermansson, O
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Cellbiologi.
    Distribution of the transcription factor Signal Transducer and Activator of Transcription 3 in the rat central nervous system and dorsal root ganglia2000Ingår i: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 853, nr 1, s. 105-114Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Signal Transducer and Activator of Transcription 3 (STAT3) is a transcription factor that acts as an intracellular signalling molecule after receptor activation by several cytokines, e.g., interleukin-6, leptin and ciliary neurotrophic factor. We have investigated the localization of STAT3 in the rat central nervous system and dorsal root ganglia. Light microscopic immunohistochemistry showed that STAT3-like immunoreactivity (STAT3-LI) was present in the nucleus and cytoplasm of neurons. STAT3-LI was seen both in cell bodies and in proximal and distal dendrites. Many structures involved in motor functions, such as the ventral horn of the spinal cord, the motor cranial nerve nuclei, the red nucleus and the Purkinje cells of the cerebellum showed STAT3-LI. STAT3-LI was also present in many regions involved in autonomic regulation, such as the intermediolateral cell column of the spinal cord, the nucleus of the solitary tract, the dorsal motor nucleus of the vagus nerve, the area postrema, the locus coeruleus, the Barrington's nucleus and the arcuate, the lateral, the dorsomedial, the ventromedial, and the paraventricular hypothalamic nuclei. Other structures showing STAT3-LI were the dorsal root ganglia, the thalamus (the anterodorsal and paraventricular nucleus), the cerebral neocortex (layer 5) and the olfactory bulb. The wide distribution of STAT3-LI in the nervous system is consistent with reports of cytokine actions in the brain, but the present findings further suggest novel roles for STAT3 in mediating influences of cytokines on specific neuronal circuits regulating motor, sensory and autonomic functions.

  • 43.
    Svensson, Samuel
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Lysophophatidic Acid Stimulates Proliferation of Cultured Smooth Muscle Cells From Human BPH.Tissue: Sildenafil and Papaverin Generate InhibitionThe Prostate2002Ingår i: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 50, s. 50-58Artikel i tidskrift (Övrig (populärvetenskap, debatt, mm))
  • 44.
    Svensson, Samuel
    Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Melanophore a2-Adrenoceptors.1993Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    The present study provides new insight into the pharmacology, the signal transduction mechanisms and the molecular biology of a2-adrenoceptors (a2-ARs) in black pigment cells (melanophores) of a teleost fish, the cuckoo wrasse (Labrus ossifagus L.). Stimulation of these receptors leads to an aggregation of intracellular pigment granules, which is the cellular mechanism underlying the ability of fishes to change color.

    The pharmacology of the melanophore a2-AR is very similar to its mammalian counterparts. However, the melanophore a2-AR is unique in one respect, UK 14,304, a potent agonist at mammalian a2-ARs, is an antagonist in melanophores.

    Noradrenaline and the selective a2-AR agonist B-HT 920 are pharmacologically heterogeneous regarding their ability to induce pigment aggregation. This may reflect that B-HT 920 and noradrenaline interact with different a2-AR sites.

    Pigment aggregation induced by a2-ARs seems to involve multiplesignaling pathways. Attenuation of intracellular cAMP production and a subsequent reduction of protein kinase A activity may serve as one mechanism, and an additional signal mechanism may involve activation of a phosphatase.

    An a2-adrenoceptor (a2p) from L. ossifagus skin mRNA was cloned. The deduced amino acid sequence showed significant homology with the human a2-ARs. When expressed in a mammalian cell line, the pharmacology of the <X2F was found to be very similar that of the in situ melanophore a2-ARs. The <X2F showed characteristics of both the human a2CIO and a2C4, indicating that <X2F may represent traces of an ancestral subtype.

    Melanin-concentrating hormone (MCH) induces pigment aggregationthrough a unique receptor. However, MCH receptors and a2-ARs might share a common signal transduction mechanism, namely attenuation of cAMP production.

    When melanophores are maintained in tissue culture media, the sensitivity to noradrenaline is increased and the sensitivity to MCH is decreased. This reciprocal change in sensitivity may be due to an increase in a2-AR coupling at the expense of MCH receptor couplingand/or to a down regulation of MCH receptors.

  • 45.
    Svensson, Samuel
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Lindgren, Sofi
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi.
    Powell, Wendy
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi.
    Green, Henrik
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi.
    Melanin inhibits cytotoxic effects of doxorubicin and daunorubicin in MOLT 4 cells2003Ingår i: Pigment Cell Research, ISSN 1755-1471, E-ISSN 1755-148X, Vol. 16, nr 4, s. 351-354Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In the present study we have developed a simple method to elucidate the melanin binding ability of different chemotherapeutic agents. The anthracyclines, doxorubicin and daunorubicin, or the alkylating agent cisplatin were preincubated with melanin (Sepia). Melanin and free drug was then separated through centrifugation and the cytotoxic effects of corresponding drug were evaluated in a MTT (3-(4,5-dimetyltiazol-2-yl)-2,5-difenyl-tetrazoliumbromide) assay using MOLT-4 cells. Our results show that melanin pretreatment shifted the IC50 value for doxorubicin from 0.06 to 0.97 ╡M and for daunorubicin from 0.04 to 0.80 pM. In contrast, the IC50 values of cisplatin was not influenced by melanin pretreatment indicating that cisplatin does not bind to melanin. By comparing equi-active concentrations from concentration-response curves with or without melanin pretreatment an approximate binding capacity of melanin could be estimated. Our results show that melanin binds about 900 nmol/mg doxorubicin and 760 nmol/mg daunorubicin. Chloroquine, which is known to bind to melanin with high affinity, was found to inhibit melanin binding of both daunorubicin and doxorubicin, thereby leading to an increased sensitivity of the anthracyclines. The clinical implications of melanin binding regarding unwanted accumulation of anthracyclines in the skin as well as chemoprotective effects against chemotherapy are discussed.

  • 46.
    Testorf, Martin
    et al.
    Linköpings universitet, Institutionen för medicinsk teknik. Linköpings universitet, Tekniska högskolan.
    Karlsson, Annika M.
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Svensson, Samuel
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Öberg, Åke
    Linköpings universitet, Institutionen för medicinsk teknik. Linköpings universitet, Tekniska högskolan.
    Lundström, Ingemar
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Tillämpad Fysik. Linköpings universitet, Tekniska högskolan.
    A model for switch-like phenomena in biological systems2001Ingår i: Biophysical Chemistry, ISSN 0301-4622, E-ISSN 1873-4200, Vol. 94, nr 1-2, s. 1-9Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We present a model for the activity of protein clusters based on a simultaneous desorption of an activator (agonist, substrate molecule, etc.) and an inactivator (antagonist, inhibitor, etc.) caused by the collision or interaction between two effector molecules (e.g. receptors, enzymes). This model gives rise to switch-like dose–response curves, which are difficult to explain by ordinary co-operativity. It fits with recent experimental results obtained on single cells. Some other interesting aspects of the model are also pointed out. The model is similar to the model used to explain steep ‘dose–response curves’ in heterogeneous catalysis, caused by the reaction between two different molecules or atoms on the surface of the catalyst.

  • 47.
    Testorf, Martin
    et al.
    Linköpings universitet, Institutionen för medicinsk teknik. Linköpings universitet, Tekniska högskolan.
    Kronstrand, Robert
    Linköpings universitet, Institutionen för medicin och hälsa, Rättskemi. Linköpings universitet, Hälsouniversitetet.
    Svensson, Samuel
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Lundström, Ingemar
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Tillämpad Fysik. Linköpings universitet, Tekniska högskolan.
    Ahlner, Johan
    Linköpings universitet, Institutionen för medicin och hälsa, Rättskemi. Linköpings universitet, Hälsouniversitetet.
    Characterization of [3H]flunitrazepam binding to melanin2001Ingår i: Analytical Biochemistry, ISSN 0003-2697, E-ISSN 1096-0309, Vol. 298, nr 2, s. 259-264Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In both clinical and forensic toxicology, the analysis of hair for drugs is an important tool to determine drug use in the past or to verify abstinence from illegal drugs during extended periods. Melanin is proposed as one of the factors that influences drug incorporation to hair and we have characterized the binding of the drug flunitrazepam to melanin in vitro. The drug was 3H labeled and melanin granules from cuttlefish, Sepia officinalis, were used according to the suggested standard for melanin studies. We observed a rapid Langmuir-like binding followed by a slower diffusion-limited binding that may be interpreted as an initial surface binding followed by deeper bulk binding. From three concentrations of melanin, with a 60-min incubation time, a mean saturation value of 180 ± 20 pmol/mg was calculated. The binding of a group of benzodiazepines and tranquilizers was compared to the binding of [3H]flunitrazepam by means of displacement experiments. These drugs showed binding characteristics similar to [3H]flunitrazepam except phenobarbital, which had a lower affinity to melanin. The method presented in this study allowed measurements with low melanin and drug concentrations and it has the strength of directly measuring the amount of drug bound to melanin, in contrast to previous indirect methods.

  • 48.
    Testorf, Martin
    et al.
    Linköpings universitet, Institutionen för medicinsk teknik. Linköpings universitet, Hälsouniversitetet.
    Roback, Kerstin
    Linköpings universitet, Institutionen för medicinsk teknik. Linköpings universitet, Tekniska högskolan.
    Lundström, Ingemar
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Tillämpad Fysik. Linköpings universitet, Tekniska högskolan.
    Svensson, Samuel
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Volume changes of individual melanosomes measured by scanning force microscopy2001Ingår i: Pigment Cell Research, ISSN 1755-1471, E-ISSN 1755-148X, Vol. 14, nr 6, s. 445-449Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Black pigment cells, melanophores, e.g. located in the epidermis and dermis of frogs, are large flat cells having intracellular black pigment granules, called melanosomes. Due to a large size, high optical contrast, and quick response to drugs, melanophores are attractive as biosensors as well as for model studies of intracellular processes; e.g. organelle transport and G-protein coupled receptors. The geometry of melanosomes from African clawed toad, Xenopus laevis, has been measured using scanning force microscopy (SFM). Three-dimensional images from SFM were used to measure height, width, and length of the melanosomes (100 from aggregated cells and 100 from dispersed cells). The volumes of melanosomes isolated from aggregated and dispersed melanophores were significantly different (P<0.05, n=200). The average ellipsoidal volume was 0.14±0.01 (aggregated) and 0.17±0.01 μm3 (dispersed), a difference of 18%. The average major diameter was 810±20 and 880±20 nm for aggregated and dispersed melanosomes, respectively. To our knowledge, this is the first time SFM has been used to study melanosomes. This may provide an alternative non-destructive technique that may be particularly suitable for studying morphological aspects of various melanin granules.

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