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Björnström, Karin
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Publications (10 of 18) Show all publications
Andersson, H., Björnström-Karlsson, K., Eintrei, C. & Sundqvist, T. (2015). Orexin A Phosphorylates the gamma-Aminobutyric Acid Type A Receptor beta(2) Subunit on a Serine Residue and Changes the Surface Expression of the Receptor in SH-SY5Y Cells Exposed to Propofol. Journal of Neuroscience Research, 93(11), 1748-1755
Open this publication in new window or tab >>Orexin A Phosphorylates the gamma-Aminobutyric Acid Type A Receptor beta(2) Subunit on a Serine Residue and Changes the Surface Expression of the Receptor in SH-SY5Y Cells Exposed to Propofol
2015 (English)In: Journal of Neuroscience Research, ISSN 0360-4012, E-ISSN 1097-4547, Vol. 93, no 11, p. 1748-1755Article in journal (Refereed) Published
Abstract [en]

Propofol activates the gamma-aminobutyric acid type A receptor (GABA(A)R) and causes a reversible neurite retraction, leaving a thin, thread-like structure behind; it also reverses the transport of vesicles in rat cortical neurons. The awakening peptide orexin A (OA) inhibits this retraction via phospholipase D (PLD) and protein kinase CE (PKCE). The human SH-SY5Y cells express both GABA(A)Rs and orexin 1 and 2 receptors. These cells are used to examine the interaction between OA and the GABAAR. The effects of OA are studied with flow cytometry and immunoblotting. This study shows that OA stimulates phosphorylation on the serine residues of the GABA(A)R beta(2) subunit and that the phosphorylation is caused by the activation of PLD and PKCE. OA administration followed by propofol reduces the cell surface expression of the GABA(A)R, whereas propofol stimulation before OA increases the surface expression. The GABA(A)R beta(2) subunit is important for receptor recirculation, and the effect of OA on propofol-stimulated cells may be due to a disturbed recirculation of the GABA(A)R. (C) 2015 Wiley Periodicals, Inc.

Place, publisher, year, edition, pages
WILEY-BLACKWELL, 2015
Keywords
orexin; propofol; GABAAR; cell signaling; AB_10675844; AB_1269637; AB_10712311; AB_2247467; AB_307187; AB_307184; AB_1566589
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-122517 (URN)10.1002/jnr.23631 (DOI)000362831800013 ()26283475 (PubMedID)
Note

Funding Agencies|County Council of Ostergotland ALF Grants; Linkoping University Hospital; Ella and Henry Stahl Research Foundation

Available from: 2015-11-09 Created: 2015-11-06 Last updated: 2018-01-10
Björnström-Karlsson, K., Turina, D., Strid, T., Sundqvist, T. & Eintrei, C. (2014). Orexin A Inhibits Propofol-Induced Neurite Retraction by a Phospholipase D/Protein Kinase C-epsilon-Dependent Mechanism in Neurons. PLoS ONE, 9(5), e0097129
Open this publication in new window or tab >>Orexin A Inhibits Propofol-Induced Neurite Retraction by a Phospholipase D/Protein Kinase C-epsilon-Dependent Mechanism in Neurons
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2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 5, p. e0097129-Article in journal (Refereed) Published
Abstract [en]

Background: The intravenous anaesthetic propofol retracts neurites and reverses the transport of vesicles in rat cortical neurons. Orexin A (OA) is an endogenous neuropeptide regulating wakefulness and may counterbalance anaesthesia. We aim to investigate if OA interacts with anaesthetics by inhibition of the propofol-induced neurite retraction. Methods: In primary cortical cell cultures from newborn rats brains, live cell light microscopy was used to measure neurite retraction after propofol (2 mu M) treatment with or without OA (10 nM) application. The intracellular signalling involved was tested using a protein kinase C (PKC) activator [phorbol 12-myristate 13-acetate (PMA)] and inhibitors of Rho-kinase (HA-1077), phospholipase D (PLD) [5-fluoro-2-indolyl des-chlorohalopemide (FIPI)], PKC (staurosporine), and a PKC epsilon translocation inhibitor peptide. Changes in PKC epsilon Ser(729) phosphorylation were detected with Western blot. Results: The neurite retraction induced by propofol is blocked by Rho-kinase and PMA. OA blocks neurite retraction induced by propofol, and this inhibitory effect could be prevented by FIPI, staurosporine and PKC epsilon translocation inhibitor peptide. OA increases via PLD and propofol decreases PKC epsilon Ser(729) phosphorylation, a crucial step in the activation of PKC epsilon. Conclusions: Rho-kinase is essential for propofol-induced neurite retraction in cortical neuronal cells. Activation of PKC inhibits neurite retraction caused by propofol. OA blocks propofol-induced neurite retraction by a PLD/PKC epsilon-mediated pathway, and PKC epsilon maybe the key enzyme where the wakefulness and anaesthesia signal pathways converge.

Place, publisher, year, edition, pages
Public Library of Science, 2014
National Category
Anesthesiology and Intensive Care
Identifiers
urn:nbn:se:liu:diva-108807 (URN)10.1371/journal.pone.0097129 (DOI)000336857400058 ()
Available from: 2014-07-07 Created: 2014-07-06 Last updated: 2017-12-05
Turina, D., Gerhardsson, H. & Björnström-Karlsson, K. (2014). Orexin A reverses propofol and thiopental induced cytoskeletal rearrangement in rat neurons. Journal of Physiology and Pharmacology, 65(4), 531-541
Open this publication in new window or tab >>Orexin A reverses propofol and thiopental induced cytoskeletal rearrangement in rat neurons
2014 (English)In: Journal of Physiology and Pharmacology, ISSN 0867-5910, E-ISSN 1899-1505, Vol. 65, no 4, p. 531-541Article in journal (Refereed) Published
Abstract [en]

Orexin A (OA) is an endogenous peptide regulating awakefulness, known to reduce anaesthesia in animals, but on cellular level its mechanisms to reverse anaesthetics are unknown. Primary cortical cell cultures from newborn rat brains are used and live cell light microscopy is performed to measure 1) neurite retraction after propofol, thiopental, barbituric acid and ketamine exposure and 2) the effect of OA application either before or after anaesthetics. Cytoskeletal reorganization is evaluated with fluorescence microscopy, protein changes are detected with Western blots and mass spectrometry is used to identify proteins after treatment with anaesthetics and/or OA. Adult rats are anaesthesized with propofol, and the cytoskeletal morphology is studied. Orexin A reverses and inhibits neurite retraction and actin ring formation induced by propofol and thiopental. No effect on retraction or actin rings was seen for ketamine (not active on gamma-aminobutiric acid (A) (GABA(A)) receptors), the non-anaesthetic barbituric acid, OA or solvents used. OA increases the tyrosine phosphorylation of a 50 kDa protein, identified as vimentin. Propofol induces an immediate granular appearance of vimentin, which OA reverses to a smooth distribution. Cytoskeletal morphology changes are also induced by propofol in vivo. All OA effects are blocked with an orexin receptor(1) (OX1) antagonist. We conclude that OA reverses the GABA(A) receptor mediated cellular effects of both propofol and thiopental in rat brain cells. The morphologic changes of actin and vimentin caused by propofol and thiopental, and the subsequent reversal by OA, deepens our understanding of the mechanisms of anaesthesia.

Place, publisher, year, edition, pages
Polish Physiological Society, 2014
Keywords
orexin A; anaesthesia; orexin receptor(1) antagonist; actin; cytoskeletal morphology; ketamine; vimentin; gamma-aminobutiric acid (A) receptor
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-112069 (URN)000343017300008 ()25179085 (PubMedID)2-s2.0-84906882999 (Scopus ID)
Note

Funding Agencies|Ostergotland County Council research foundation; Henry and Ella Stahl Research Foundation; Valter and Gertrud Gryhlin Foundation; Linkoping Society of Medicine

Available from: 2014-11-17 Created: 2014-11-13 Last updated: 2017-12-05
Appelqvist, H., Sandin, L., Björnström, K., Saftig, P., Garner, B., Öllinger, K. & Kågedal, K. (2012). Sensitivity to Lysosome-Dependent Cell Death is Directly Regulated by Lysosomal Cholesterol Content. PLoS ONE, 7(11)
Open this publication in new window or tab >>Sensitivity to Lysosome-Dependent Cell Death is Directly Regulated by Lysosomal Cholesterol Content
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2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 11Article in journal (Refereed) Published
Abstract [en]

Alterations in lipid homeostasis are implicated in several neurodegenerative diseases, although the mechanisms responsible are poorly understood. We evaluated the impact of cholesterol accumulation, induced by U18666A, quinacrine or mutations in the cholesterol transporting Niemann-Pick disease type C1 (NPC1) protein, on lysosomal stability and sensitivity to lysosome-mediated cell death. We found that neurons with lysosomal cholesterol accumulation were protected from oxidative stress-induced apoptosis. In addition, human fibroblasts with cholesterol-loaded lysosomes showed higher lysosomal membrane stability than controls. Previous studies have shown that cholesterol accumulation is accompanied by the storage of lipids such as sphingomyelin, glycosphingolipids and sphingosine and an up regulation of lysosomal associated membrane protein-2 (LAMP-2), which may also influence lysosomal stability. However, in this study the use of myriocin and LAMP deficient fibroblasts excluded these factors as responsible for the rescuing effect and instead suggested that primarily lysosomal cholesterol content determined the cellular sensitivity to toxic insults. Further strengthening this concept, depletion of cholesterol using methyl-β-cyclodextrin or 25-hydroxycholesterol decreased the stability of lysosomes and cells became more prone to undergo apoptosis. In conclusion, cholesterol content regulated lysosomal membrane permeabilization and thereby influenced cell death sensitivity. Our data suggests that lysosomal cholesterol modulation might be used as a therapeutic strategy for conditions associated with accelerated or repressed apoptosis.

Place, publisher, year, edition, pages
Public Library of Science, 2012
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-85004 (URN)10.1371/journal.pone.0050262 (DOI)000311885300096 ()23166840 (PubMedID)
Note

Funding Agencies|Swedish Research Council|2010-3463|Deutsche Forschungsgemeinschaft||foundation of Olle Engqvist||foundation of Ake Wiberg||

Available from: 2012-10-30 Created: 2012-10-30 Last updated: 2017-12-07Bibliographically approved
Turina, D. & Björnström, K. (2011). Mechanisms of general anesthetic action: Focus on the cellular network. TRANSLATIONAL NEUROSCIENCE, 2(2), 168-175
Open this publication in new window or tab >>Mechanisms of general anesthetic action: Focus on the cellular network
2011 (English)In: TRANSLATIONAL NEUROSCIENCE, ISSN 2081-3856, Vol. 2, no 2, p. 168-175Article in journal (Refereed) Published
Abstract [en]

The discovery of general anesthetics had a tremendous impact on development of surgery and medicine in general, during the last century. Despite the widespread use of general anesthetics, the mechanisms by which they produce their effects in the central nervous system are still poorly understood. Over the past decade, several new findings have contributed significantly to a better understanding of general anesthetic mechanisms. The current review summarizes recent data on different anesthetic neuronal targets that might be involved in the mechanism of action of general anesthetics, giving special attention to the importance of binding pockets for anesthetics within transmembrane receptors and cellular signaling leading to morphological changes of neuronal cells. Several lines of evidence suggest that disruption in brain network connectivity is important for anaesthesia-induced loss of consciousness and this is discussed in relation to morphological changes.

Place, publisher, year, edition, pages
VERSITA, SOLIPSKA 14A-1, 02-482 WARSAW, POLAND, 2011
Keywords
Theories of anesthetic action, Signaling cascade, GABA(A) receptor, NMDA receptors, Brain connectivity
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-74656 (URN)10.2478/s13380-011-0022-5 (DOI)000298886600010 ()
Available from: 2012-02-03 Created: 2012-02-03 Last updated: 2012-03-20
Turina, D., Björnström-Karlsson, K., Sundqvist, T. & Eintrei, C. (2011). Propofol alters vesicular transport in rat cortical neuronalcultures. Journal of Physiology and Pharmacology, 62(1), 119-124
Open this publication in new window or tab >>Propofol alters vesicular transport in rat cortical neuronalcultures
2011 (English)In: Journal of Physiology and Pharmacology, ISSN 0867-5910, E-ISSN 1899-1505, Vol. 62, no 1, p. 119-124Article in journal (Refereed) Published
Abstract [en]

Neuronal intracellular transport is performed by motor proteins, which deliver vesicles, organelles and proteins along cytoskeletal tracks inside the neuron. We have previously shown that the anesthetic propofol causes dose- and time-dependent, reversible retraction of neuronal neurites. We hypothesize that propofol alters the vesicular transport of cortical neurons due to this neurite retraction. Primary cultures of co-cultivated rat cortical neurons and glial cells were exposed to either 2 mu M propofol, control medium or the lipid vehicle, in time-response experiments. Reversibility was tested by washing propofol off the cells. The role of the GABA(A) receptor (GABA(A)R) was assessed with the GABA(A)R antagonist gabazine. Vesicles were tracked using differential interference contrast video microscopy. Propofol caused a retrograde movement in 83.4 +/- 5.2% (mean +/- S.E.M.) of vesicles, which accelerated over the observed time course (0.025 +/- 0.012 mu m.s(-1)). In control medium, vesicles moved predominantly anterograde (84.6 +/- 11.1%) with lower velocity (0.011 +/- 0.004 mu m.s(-1)). Cells exposed to the lipid vehicle showed the same dynamic characteristics as cells in control medium. The propofol-induced effect on vesicle transport was reversible and blocked by the GABA(A)R antagonist gabazine in low concentration. Our results show that propofol causes a reversible, accelerating vesicle movement toward the neuronal cell body that is mediated via synaptic GABA(A)R. We have previously reported that propofol initiates neurite retraction, and we propose that propofol causes vesicle movement by retrograde flow of cytoplasm from the narrowed neurite.

Place, publisher, year, edition, pages
Polish Physiological Society, 2011
Keywords
anesthetics intravenously, brain, cellular mechanism, cerebral cortex, neurotransmission effects, pharmacology, propofol, theories of anesthetic action, vesicular transport
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-67967 (URN)000289542300014 ()
Available from: 2011-05-04 Created: 2011-05-04 Last updated: 2017-12-11Bibliographically approved
Björnström, K., Turina, D., Loverock, A., Lundgren, S., Wijkman, M., Lindroth, M. & Eintrei, C. (2008). Characterisation of the signal transduction cascade caused by propofol in rat neurons: From the GABAA receptor to the cytoskeleton. Journal of Physiology and Pharmacology, 59(3), 617-632
Open this publication in new window or tab >>Characterisation of the signal transduction cascade caused by propofol in rat neurons: From the GABAA receptor to the cytoskeleton
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2008 (English)In: Journal of Physiology and Pharmacology, ISSN 0867-5910, E-ISSN 1899-1505, Vol. 59, no 3, p. 617-632Article in journal (Refereed) Published
Abstract [en]

The anaesthetic propofol interacts with the GABAA receptor, but its cellular signalling pathways are not fully understood. Propofol causes reorganisation of the actin cytoskeleton into ring structures in neurons. Is this reorganisation a specific effect of propofol as apposed to GABA, and which cellular pathways are involved? We used fluorescence-marked actin in cultured rat neurons to evaluate the percentage of actin rings caused by propofol or GABA in combination with rho, rho kinase (ROK), PI3-kinase or tyrosine kinase inhibitors, with or without the presence of extracellular calcium. Confocal microscopy was performed on propofol-stimulated cells and changes in actin between cellular compartments were studied with Western blot. Propofol (3 μg·ml-1), but not GABA (5 μM), caused transcellular actin ring formation, that was dependent on influx of extracellular calcium and blocked by rho, ROK, PI3-kinase or tyrosine kinase inhibitors. Propofol uses rho/ROK to translocate actin from the cytoskeleton to the membrane and its actin ring formation is dependent on an interaction site close to the GABA site on the GABAA receptor. GABA does not cause actin rings, implying that this is a specific effect of propofol.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-43536 (URN)74109 (Local ID)74109 (Archive number)74109 (OAI)
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2017-12-13
Turina, D., Loitto, V., Björnström, K., Sundqvist, T. & Eintrei, C. (2008). Propofol causes neurite retraction in neurons. Paper presented at SFAI möte Uppsala.
Open this publication in new window or tab >>Propofol causes neurite retraction in neurons
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2008 (English)Conference paper, Published paper (Refereed)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-69414 (URN)
Conference
SFAI möte Uppsala
Available from: 2011-06-27 Created: 2011-06-27 Last updated: 2011-07-01
Turina, D., Loitto, V., Björnström, K., Sundqvist, T. & Eintrei, C. (2008). Propofol causes neurite retraction in neurons. British Journal of Anaesthesia, 101(3), 374-379
Open this publication in new window or tab >>Propofol causes neurite retraction in neurons
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2008 (English)In: British Journal of Anaesthesia, ISSN 0007-0912, E-ISSN 1471-6771, Vol. 101, no 3, p. 374-379Article in journal (Refereed) Published
Abstract [en]

Background The mechanism by which anaesthetic agents produce general anaesthesia is not yet fully understood. Retraction of neurites is an important function of individual neurones and neural plexuses during normal and pathological conditions, and it has been shown that such a retraction pathway exists in developing and mature neurones. We hypothesized that propofol decreases neuronal activity by causing retraction of neuronal neurites.

Methods Primary cultures of rat cortical neurones were exposed in concentration– and time–response experiments to 0.02, 0.2, 2, and 20 µM propofol or lipid vehicle. Neurones were pretreated with the GABAA receptor (GABAAR) antagonist, bicuculline, the myosin II ATPase activity inhibitor, blebbistatin, and the F-actin stabilizing agent, phalloidin, followed by administration of propofol (20 µM). Changes in neurite retraction were evaluated using time-lapse light microscopy.

Results Propofol caused a concentration- and time-dependent reversible retraction of cultured cortical neurone neurites. Bicuculline, blebbistatin, and phalloidin completely inhibited propofol-induced neurite retraction. Images of retracted neurites were characterized by a retraction bulb and a thin trailing membrane remnant.

Conclusions Cultured cortical rat neurones retract their neurites after exposure to propofol in a concentration- and time-dependent manner. This retraction is GABAAR mediated, reversible, and dependent on actin and myosin II. Furthermore, the concentrations and times to full retraction and recovery correspond to those observed during propofol anaesthesia.

Place, publisher, year, edition, pages
Oxford, UK: Oxford University Press, 2008
Keywords
Anaesthetics i.v., propofol; brain, GABA rat; theories of anaesthetic action, cellular mechanisms
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-78010 (URN)10.1093/bja/aen185 (DOI)000259093300014 ()
Available from: 2012-06-04 Created: 2012-06-04 Last updated: 2017-12-07Bibliographically approved
Turina, D., Björnström, K. & Eintrei, C. (2006). Propofol reglerar ansamling av perinukleära GABAa receptorer i korikala råttneuron. In: SFAI-möte,2006.
Open this publication in new window or tab >>Propofol reglerar ansamling av perinukleära GABAa receptorer i korikala råttneuron
2006 (Swedish)In: SFAI-möte,2006, 2006Conference paper, Published paper (Other academic)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-36928 (URN)33073 (Local ID)33073 (Archive number)33073 (OAI)
Available from: 2009-10-10 Created: 2009-10-10
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