GPR55 is a G protein-coupled receptor. Recently, we obtained evidence that lysophosphatidylinositol (LPI) is a possible endogenous ligand for GPR55. However, no information is currently available concerning the biological activities of the individual molecular species of LPI. Furthermore, little is known concerning the levels as well as the molecular species of LPI in mammalian tissues. In this study, we first examined whether LPI is present in rat brain. We found that rat brain contains 37.5 nmol/g tissue of LPI; the most predominant fatty acyl moiety is stearic acid (50.5%) followed by arachidonic acid (22.1%). We next compared the biological activities of various molecular species of LPI and related molecules using HEK293 cells expressing GPR55. We found that the level of biological activity of the 2-arachidonoyl species is markedly higher than those of others. These results strongly suggest that the 2-arachidonoyl species of LPI is the true natural ligand for GPR55.
Lysophosphatidylinositol (LPI) is an endogenous ligand for GPR55, a putative novel type of cannabinoid receptor. In this study, we first examined the effects of LPI on p38 mitogen-activated protein kinase in HEK293 cells expressing GPR55. LPI induced the rapid phosphorylation of p38 mitogen-activated protein kinase in GPR55-expressing cells. No apparent effect was observed in the vector-transfected cells. The exposure of GPR55-expressing cells to LPI also triggered the phosphorylation of activating transcription factor 2 downstream of the p38 mitogen-activated protein kinase. Treatment of the cells with Y-27632 [a Rho-associated kinase (ROCK) inhibitor] blocked the LPI-induced phosphorylation of p38 mitogen-activated protein kinase and activating transcription factor 2, suggesting that the Rho-ROCK pathway is involved in these cellular responses. Notably, GPR55 was found to be abundantly expressed in lymphoid organs such as the spleen and thymus. We obtained evidence that rapid phosphorylation of p38 mitogen-activated protein kinase and activating transcription factor 2 also takes place in IM-9 lymphoblastoid cells, which naturally express GPR55, after stimulation with LPI. These results suggest that GPR55 and its endogenous ligand LPI play essential roles in the homoeostatic responses to stress signals in several mammalian tissues and cells including certain types of immune cells.
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