Endothelin-1 activates ETA receptors to increase intracellular calcium in model sensory neurons

Endothelin-1 (ET-1) induces endothelin-A (ETA) receptor-mediated pain and selective excitation of nociceptors. Here we studied ET-1-induced changes in intracellular calcium (Cain) in Fura-2 loaded mouse neuroblastoma–rat dorsal root ganglion hybrid cells (ND7/104). ET-1 (1–400 nM) induced concentration-dependent, transient increases in Cain, probably of intracellular source. Responses to repeated application declined with increasing ET-1 concentration, implying receptor desensitization. Treatment of cells with the selective ETA receptor antagonist, BQ-123, produced a dose-dependent inhibition of the response that was 20% of ET-1 alone (IC50 = 20 nM, KI = 7 nM). No inhibition of the calcium response was observed with the selective ETB antagonist, BQ-788 (10–1000 nM). These results demonstrate that ET-1 induces dose- and ETA receptor-dependent release of Cain in nociceptor-like neurons, and permit further examination of the pathways that underlie ET-1-induced pain signaling.