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Different proliferative responses of Gi/o-protein-coupled receptors in human myometrial smooth muscle cells: a possible role of calcium
Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Obstetrics and gynecology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Gynecology and Obstetrics in Linköping.
Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
1998 (English)In: Journal of Molecular Neuroscience, ISSN 0895-8696, Vol. 11, no 1, 11-21 p.Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
1998. Vol. 11, no 1, 11-21 p.
Keyword [en]
Uterus, smooth muscle cells, G protein-coupled receptors, DNA synthesis
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-13736DOI: 10.1385/JMN:11:1:11OAI: oai:DiVA.org:liu-13736DiVA: diva2:21226
Available from: 2006-01-17 Created: 2006-01-17 Last updated: 2009-08-20
In thesis
1. Lysophosphatidic acid: Physiological effects and structure-activity relationships
Open this publication in new window or tab >>Lysophosphatidic acid: Physiological effects and structure-activity relationships
2002 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Lipids havepreviously been considered primarily as building blocks of the cell membrane, but are now also recognized as important cell signaling molecules. Lysophosphatidic acid (LPA) is a glycerophospholipid consisting of a phosphate head group, a linker region, and a lipophilic tail. LPA has earlier been shown to exert a diversity of cellular effects such as aggregation, apoptosis, contraction, migration, and proliferation. The effects of LPA are elicited by activation of its cognate G protein-coupled receptors LPA1, LPA2, and LPA3. In the present study we have used cultures of human smooth muscle cells (SMCs) and erythroleukemia cells (HEL), and isolated human platelets to characterize physiological effects of LPA compared with adrenaline and noradrenaline as well as structure-activity relationships of LPA. SMCs were isolated from biopsies of human myometrium obtained at cesarean sections. We show that cultured myometrial SMCs express multiple LPA and α2-adrenergic receptor subtypes. Treatment of SMCs with LPA and noradrenaline resulted in increases in proliferation. However, LPA elicits a much more pronounced stimulatory effect than noradrenaline. The ability to increase calcium might be one explanation why LPA is more effective. Further studies indicated that several pathways mediate the growth stimulatory effect of LPA where transactivation of epidermal growth factor receptors through matrix metalloproteinases as well as calcium/calmodulin-dependent protein kinases appears to be important. LPA enantiomers and LPA analogues were synthesized and characterized due to their capacity to increase calcium in HEL cells. Our study is the first to show that both natural (R) and unnatural (S) LPA enantiomers are capable of stimulating cells, suggesting LPA receptors are not stereoselective. Moreover, we have synthesized a LPA analogue with higher maximal effect than LPA by reducing the hydrocarbon chain length. In platelets we demonstrated that LPA is a weak calciumelevating compound which failed to stimulate aggregation. However, in combination with adrenaline, another weak platelet agonist, a complete aggregatory response was obtained in blood from some healthy individuals. These results are important since platelet activation is a key step in distinguishing normal from pathological hemostasis. Since LPA is present at high concentrations in atherosclerotic lesions, the synergistic effect of LPA and adrenaline might be a new risk factor for arterial thrombosis.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2002. 100 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 751
Keyword
Lysophospholipids pharmacology, physiology, structure-activity relationship, muscle, smooth, drug effects, myometrium, norepinephrine, epinephrine, signal transduction
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-5237 (URN)91-7373-192-7 (ISBN)
Public defence
2002-11-08, Berzeliussalen, Campus US, Linköpings universitet, Linköping, 13:00 (English)
Opponent
Supervisors
Note
On the day of the public defence the status of the article IV was: Submitted for publication.Available from: 2006-01-17 Created: 2006-01-17 Last updated: 2012-01-25Bibliographically approved

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Nilsson, Ulrika K.Grenegård, MagnusBerg, GöranSvensson, Samuel P.S.

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