IMMORTALIZED SCHWANN-CELLS EXPRESS ENDOTHELIN RECEPTORS COUPLED TO ADENYLYL-CYCLASE AND PHOSPHOLIPASE-C

Endothelins (ETs) are potent regulators of renal, cardiovascular and e ndocrine functions and act as neurotransmitters in the CNS. Here we re port that immortalized Schwann cells express receptors for ETs and cha racterize some of the cellular events triggered by their activation. S pecific binding of [I-125]-ET-1 to Schwann cell membranes was inhibite d by ET-1 and the ETB-selective agonists ET-3, sarafotoxin 6c and [Ala (1,3,11,15)]-ET-1 with IC50cor values ranging between 2 and 20 nM. No competition was observed with the ETA receptor-selective antagonist BQ 123. Incubation of [H-3]-inositol pre-labeled Schwann cells with ET-I, ET-3 or sarafotoxin 6c elicited a concentration-dependent increase in the release of IP1 that reached a plateau at approximately 100 nM. Th e efficacy of [Ala(1,3,11,15)]-ET-1 (a linear peptide analog of ET-1) was half of that corresponding to ET-1. These stimulatory effects were partially blocked by pre-incubation with pertussis toxin. When Schwan n cells were incubated in the presence of 100 nM ET-1 or ET-3 there wa s a significant inhibition of basal and isoproterenol-stimulated cAMP levels. The inhibitory effects of sarafotoxin 6c and [Ala(1,3,11,15)]- ET-1 On isoproterenol-stimulated cAMP levels were similar to that obse rved with ET-1. Pre-incubation with pertussis toxin completely prevent ed this effect. These observations indicate that immortalized Schwann cells express receptors for ET peptides (predominantly ETB) coupled to modulation of phospholipase C and adenylyl cyclase activities. The ac tions of ETs on Schwann cells provide a novel example of the influence of vascular factors on nerve function.