Endothelins regulate arachidonic acid release and mitogen-activated protein kinase activity in Schwann cells

Immortalized rat Schwann cells (ISC) express endothelin (ET) receptors coup led to inhibition of adenylyl cyclase and stimulation of phospholipase C (P LC). These effects precede phenotypic changes and increased DNA synthesis. We have investigated the role of ETs in the regulation of arachidonic acid (AA) release and mitogen-activated protein kinases (MAPKs). Both ET-1 and E T-3 increased AA release in ISC. This effect was sensitive to the phospholi pase A(2) (PLA(2)) inhibitors E-6-(bromomethylene)tetrahydro-3-(1-naphthale nyl)-2H-pyran-2-one and arachidonyl-trifluoromethyl ketone but was insensit ive to inhibitors of PLC or phospholipase D-dependent diacyl-glycerol gener ation. ET-1-dependent AA release was also unaffected by removal of extracel lular Ca2+ and blocking the concomitant elevation in [Ca2+](i), consistent with participation of a Ca2+-independent PLA(2). Treatment of ISC with ETs also resulted in activation of extracellular signal-regulated kinase, c-Jun -NH2-terminal kinase (JNK), and p38 MAPK, A cause-effect relationship betwe en agonist-dependent AA release and stimulation of MAPKs, but not the oppos ite, was suggested by activation of JNK by exogenous AA and by the observat ion that inhibition of MAPK kinase or p38 MAPK was inconsequential to ET-1- induced AA release. Similar effects of ETs on AA release and MAPK activity were observed in cultures expanded from primary SC and in ISC. Regulation o f these effecters may mediate the control of proliferation and differentiat ion of SC by ETs during peripheral nerve development and regeneration.