Endothelins Regulate Arachidonic Acid Release and Mitogen‐Activated Protein Kinase Activity in Schwann Cells

: Immortalized rat Schwann cells (iSC) express endothelin(ET) receptors coupled to inhibition of adenylyl cyclase and stimulation ofphospholipase C (PLC). These effects precede phenotypic changes and increasedDNA synthesis. We have investigated the role of ETs in the regulation ofarachidonic acid (AA) release and mitogen‐activated protein kinases (MAPKs).Both ET‐1 and ET‐3 increased AA release in iSC. This effect was sensitive tothe phospholipase A2 (PLA2) inhibitorsE‐6‐(bromomethylene)tetrahydro‐3‐(1‐naphthalenyl)‐2H‐pyran‐2‐oneand arachidonyl‐trifluoromethyl ketone but was insensitive to inhibitors ofPLC or phospholipase D‐dependent diacylglycerol generation. ET‐1‐dependent AArelease was also unaffected by removal of extracellular Ca2+ andblocking the concomitant elevation in [Ca2+]i,consistent with participation of a Ca2+‐independentPLA2. Treatment of iSC with ETs also resulted in activation ofextracellular signal‐regulated kinase, c‐Jun‐NH2‐terminal kinase(JNK), and p38 MAPK. A cause‐effect relationship between agonist‐dependent AArelease and stimulation of MAPKs, but not the opposite, was suggested byactivation of JNK by exogenous AA and by the observation that inhibition ofMAPK kinase or p38 MAPK was inconsequential to ET‐1‐induced AA release.Similar effects of ETs on AA release and MAPK activity were observed incultures expanded from primary SC and in iSC. Regulation of these effectorsmay mediate the control of proliferation and differentiation of SC by ETsduring peripheral nerve development and regeneration.