Characterization of lysophosphatidic acid and sphingosine-1-phosphate-mediated signal transduction in rat cortical oligodendrocytes

Lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) have been proposed to play a key role in oligodendrocyte maturation and myelinogenesis. In this study, we examined lysophospholipid receptor gene expression in differentiated rat oligodendrocyte cultures and signaling downstream of lysophospholipid receptor activation by LPA and S1P. Differentiated oligodendrocytes express mRNAs encoding lysophospholipid receptors with the relative abundance of lpa1>s1p5>s1p1=s1p2=lpa3>s1p3. LPA and S1P transiently increased phosphorylation of extracellular signal-regulated kinase (ERK) with EC50 values of 956 and 168 nM, respectively. LPA- and S1P-induced ERK phosphorylation was dependent on the activation of mitogen-activated protein kinase (MAPK), phospholipase C (PLC), and protein kinase C (PKC), but was insensitive to pertussis toxin (PTX). LPA increased intracellular calcium levels in oligodendrocytes and these increases were partially blocked by a PLC inhibitor but not by PTX. In contrast, S1P was not found to induce measurable changes of intracellular calcium. These results taken together suggest that lysophospholipid receptor activation involves receptor coupling to heterotrimeric Gq subunits with consequent activation of PLC, PKC, and MAPK pathways leading to ERK phosphorylation.