Intracellular Ca2+ stores are functionally maintained by Ca2+ uptake and release processes, both of which are electrogenic events. It has been predicted that counter-ion movements may balance the membrane potential to establish efficient Ca2+ release and uptake mechanisms in intracellular stores. However, molecular components mediating counter-ionic currents are unknown. We recently identified TRIC channel subtypes derived from distinct genes, namely TRIC-A and TRIC-B. TRIC channels are distributed to the endo/sarcoplasmic reticulum (ER/SR) and nuclear membranes in various cell types; TRIC-A is preferentially expressed in excitable tissues, while ubiquitous expression is observed for TRIC-B. TRIC channels are composed of ~300 amino acid residues, and contain three putative membrane-spanning segments to form a bullet-shaped homo-trimeric assembly. Both purified native and recombinant TRIC subtypes form functional monovalent cation-selective channels in a lipid bilayer reconstitution system. Based on the electrophysiological data indicating that TRIC channels behave as K+ channels under intracellular conditions, we have been examining the physiological roles of the TRIC subtypes using the gene-knockout and transgenic mice. Animal experiments were conducted with approval of the Animal Research Committee according to Kyoto University regulations. All surgical procedures were performed under pentobarbital anesthesia (50 mg/kg, intraperitoneal). Double-knockout mice lacking both TRIC subtypes show embryonic heart failure, and Ca2+ release during excitation-contraction coupling is compromised in the mutant cardiomyocytes. Tric-a-knockout mice develop hypertension resulting from vascular hypertonicity, and the knockout vascular smooth muscle exhibits depolarized resting potential due to insufficient spontaneous Ca2+ sparks for inducing hyperpolarization. In contrast, mutant mice carrying the smooth muscle-specific Tric-a transgene develop hypotension. Moreover, Tric-b-knockout mice show respiratory failure at birth and Ca2+ release essential for surfactant handling is impaired in the mutant alveolar epithelial cells. Therefore, TRIC channels seem to mediate ER/SR counter-K+ movements in part to facilitate physiological Ca2+ release mediated by ryanodine and inositol-trisphosphate receptor channels in various cell types. This poster highlights the Tric-a-knockout hypertension and Tric-a-transgenic hypotension, and sets out the proposed physiological functions of TRIC channel subtypes in vascular smooth muscle cells.