Immortalized Schwann Cells Express Endothelin Receptors Coupled to Adenylyl Cyclase and Phospholipase C

Endothelins (ETs) are potent regulators of renal, cardiovascular and endocrine functions and act as neurotransmitters in the CNS. Here we report that immortalized Schwann cells express receptors for ETs and characterize some of the cellular events triggered by their activation. Specific binding of ¹²⁵I]-ET-1 to Schwann cell membranes was inhibited by ET-1 and the ET_B-selective agonists ET-3, sarafotoxin 6c and A1a^1,3,11,15]-ET-1 with IC_50cor values ranging between 2 and 20 nM. No competition was observed with the ET_A receptor-selective antagonist BQ123. Incubation of ³H]-inositol pre-labeled Schwann cells with ET-1, ET-3 or sarafotoxin 6c elicited a concentration-dependent increase in the release of IP₁ that reached a plateau at approximately 100 nM. The 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 Schwann cells were incubated in the presence of 100 nM ET-1 or ET-3 there was 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 observed with ET-1. Pre-incubation with pertussis toxin completely prevented this effect. These observations indicate that immortalized Schwann cells express receptors for ET peptides (predominantly ET_B) coupled to modulation of phospholipase C and adenylyl cyclase activities. The actions of ETs on Schwann cells provide a novel example of the influence of vascular factors on nerve function.