Involvement of extracellular Ca2+ influx through voltage-independent Ca2+ channels in endothelin-1 function

This article reviews the types and roles of voltage-independent Ca2+ channels involved in the endothelin-1 (ET-1)-induced functional responses such as vascular contraction, cell proliferation, and intracellular Ca2+-dependent signaling pathways and discusses the molecular mechanisms for the activation of voltage-independent Ca2+ channels by ET-1. ET-1 activates some types of voltage-independent Ca2+ channels, such as Ca2+-permeable nonselective cation channels (NSCCs) and store-operated Ca2+ channels (SOCC). Extracellular Ca2+ influx through these voltage-independent Ca2+ channels plays essential roles in ET-1-induced vascular contraction, cell proliferation, activation of epidermal growth factor receptor tyrosine kinase, regulation of proline-rich tyrosine kinase, and release of arachidonic acid. The experiments using various constructs of endothelin receptors reveal the importance of Gq and G12 families in activation of these Ca2+ channels by ET-1. These findings provide a potential therapeutic mechanism of a functional interrelationship between Gq/G12 proteins and voltage-independent Ca2+ channels in the pathophysiology of ET-1, such as in chronic heart failure, hypertension, and cerebral vasospasm.