Facilitated Hyperpolarization Signaling in Vascular Smooth Muscle-overexpressing TRIC-A Channels

The TRIC channel subtypes, namely TRIC-A and TRIC-B, are intracellular monovalent cation-specific channels and likely mediate counterion movements to support efficient Ca 2+ release from the sarco/endoplasmic reticulum. Vascular smooth muscle cells (VSMCs) contain both TRIC subtypes and two Ca 2+ release mechanisms; incidental opening of ryanodine receptors (RyRs) generates local Ca 2+ sparks to induce hyperpolarization and relaxation, whereas agonist-induced activation of inositol trisphosphate receptors produces global Ca 2+ transients causing contraction. Tric-a knock-out mice develop hypertension due to insufficient RyR-mediated Ca 2+ sparks in VSMCs. Here we describe transgenic mice overexpressing TRIC-A channels under the control of a smooth muscle cell-specific promoter. The transgenic mice developed congenital hypotension. In Tric-a -overexpressing VSMCs from the transgenic mice, the resting membrane potential decreased because RyR-mediated Ca 2+ sparks were facilitated and cell surface Ca 2+ -dependent K + channels were hyperactivated. Under such hyperpolarized conditions, L-type Ca 2+ channels were inactivated, and thus, the resting intracellular Ca 2+ levels were reduced in Tric-a -overexpressing VSMCs. Moreover, Tric-a overexpression impaired inositol trisphosphate-sensitive stores to diminish agonist-induced Ca 2+ signaling in VSMCs. These altered features likely reduced vascular tonus leading to the hypotensive phenotype. Our Tric-a -transgenic mice together with Tric-a knock-out mice indicate that TRIC-A channel density in VSMCs is responsible for controlling basal blood pressure at the whole-animal level. Background: TRIC channels likely mediate counter-K + movements during store Ca 2+ release, but their roles are unknown in many cell types. Results: Smooth muscle-specific Tric-a -transgenic mice developed hypotension due to facilitated hyperpolarization signaling in vascular muscle. Conclusion: TRIC-A channels facilitate Ca 2+ spark generation in vascular muscle. Significance: TRIC-A channels may have unexplained roles in store Ca 2+ distribution but provide a potential pharmaceutical target for vasomodulation.