Abstract
ResultsThe lysophosphatidic acid receptors LPA1, LPA2, and LPA3 were individually expressed in C9 cells and their signaling and regulation were studied. Agonist-activation increases intracellular calcium concentration in a concentration-dependent fashion. Phorbol myristate acetate markedly inhibited LPA1- and LPA3-mediated effect, whereas that mediated by LPA2 was only partially diminished; the actions of the phorbol ester were inhibited by bisindolylmaleimide I and by overnight incubation with the protein kinase C activator, which leads to down regulation of this protein kinase. Homologous desensitization was also observed for the three LPA receptors studied, with that of LPA2 receptors being consistently of lesser magnitude; neither inhibition nor down-regulation of protein kinase C exerted any effect on homologous desensitization. Activation of LPA1–3 receptors induced ERK 1/2 phosphorylation; this effect was markedly attenuated by inhibition of epidermal growth factor receptor tyrosine kinase activity, suggesting growth factor receptor transactivation in this effect. Lysophosphatidic acid and phorbol myristate acetate were able to induce LPA1–3 phosphorylation, in time- and concentration-dependent fashions. It was also clearly observed that agonists and protein kinase C activation induced internalization of these receptors. Phosphorylation of the LPA2 subtype required larger concentrations of these agents and its internalization was less intense than that of the other subtypes.ConclusionOur data show that these three LPA receptors are phosphoproteins whose phosphorylation state is modulated by agonist-stimulation and protein kinase C-activation and that differences in regulation and cellular localization exist, among the subtypes.
Highlights
Lysophosphatidic acid (LPA) is one of the so-called, “bioactive lipids”, that participates in cell metabolism and as an autacoid or local hormone, communicating cells
Our data show that these three LPA receptors are phosphoproteins whose phosphorylation state is modulated by agonist-stimulation and protein kinase C-activation and that differences in regulation and cellular localization exist, among the subtypes
LPA actions are mainly exerted through a family of G protein-coupled receptors (GPCRs), that is, the LPA receptors, comprising six members that are currently designated LPA1–6; the possibility that GPR87 could be a member of this family has been suggested, i. e., such as LPA7 [1,2,3,4,5,6]
Summary
Lysophosphatidic acid (LPA) is one of the so-called, “bioactive lipids”, that participates in cell metabolism and as an autacoid or local hormone, communicating cells. E., such as LPA7 [1,2,3,4,5,6] Of these receptors, LPA1, LPA2 and LPA3 are phylogenetically related among themselves and with those of other bioactive lipids (the endothelial differentiation gene [“edg”] family); the remaining LPA receptors are distant phylogenetically from these and are more closely related with the purinergic receptor family [1,2,3,4,5,6,7]. LPA1, LPA2 and LPA3 are phylogenetically related among themselves and with those of other bioactive lipids (the endothelial differentiation gene [“edg”] family); the remaining LPA receptors are distant phylogenetically from these and are more closely related with the purinergic receptor family [1,2,3,4,5,6,7] Evolutionary aspects of these receptors, among vertebrates, have been recently reported [7]. LPA activates the TRPV1 ion channel involved in the control of body temperature and nociception [9]
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