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Lack of stereospecificity in lysophosphatidic acid enantiomerinduced calcium mobilization in human erythroleukemia cells
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 Physics, Chemistry and Biology.
Linköping University, Department of Clinical and Experimental Medicine, Cellbiology. Linköping University, Faculty of Health Sciences.
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2003 (English)In: Lipids, ISSN 0024-4201, Vol. 38, no 10, 1057-1064 p.Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
2003. Vol. 38, no 10, 1057-1064 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-13739OAI: oai:DiVA.org:liu-13739DiVA: diva2:21229
Available from: 2006-01-17 Created: 2006-01-17
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)
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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.Andersson, Rolf G. G.Ekeroth, JohanHallin, Elisabeth C.Konradsson, PeterLindberg, JanSvensson, Samuel P.S.

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