Hypotension in SM-Specific TRIC-A-Transgenic Mice

Abstract

TRIC (trimeric intracellular cation) channel subtypes, namely TRIC-A and TRIC-B, likely mediate counter-ion movements coupled with rapid Ca2+ release from intracellular stores in various cell types. The Tric-a-knockout mice suffered from hypertension due to enhanced myogenic tone in resistance arteries. Conversely, smooth muscle (SM)-specific Tric-a-transgenic mice developed hypotension. To maintain vascular tonus, two Ca2+ release mechanisms are functioning in vascular smooth muscle cells (VSMCs); incidental opening of ryanodine receptors (RyRs) generates local Ca2+ sparks to induce hyperpolarization, while agonist-induced activation of inositol trisphosphate receptors (IP3Rs) evokes global Ca2+ transients causing contraction.To investigate the mechanism of hypotension in the Tric-a-transgenic mice, we performed Ca2+ imaging and Ca2+ spark measurements. Mutant VSMCs from the transgenic mice showed elevated Ca2+ spark generation, enhanced spontaneous transient outward currents (STOCs) and lowered resting Ca2+ levels.The observation may suggest that overexpression of TRIC-A channels activates RyRs and enhances hyperpolarization signaling generated by functional coupling between RyRs and BK channels in VSMCs. In this situation, deactivated voltage-dependent Ca2+ channels may reduce resting Ca2+ levels and spontaneous tonus in the mutant VSMCs.