TRICチャネルと高血圧

The Roles of Calcium and Phosphorus in Cardiovascular Diseases. TRIC channel and hypertension.

　細胞内K＋チャネルとして機能するTRIC（trimeric intracellular cation）サブタイプには，小胞体Ca2＋放出を促進する生理的役割が示唆される。血管平滑筋にてリアノジン受容体を介して小胞体よりCa2＋が放出されると，局所的なCa2＋スパークの発生に伴い細胞表層膜のK＋透過性が亢進し，過分極と筋弛緩が誘導される。TRIC-A欠損マウスは血管緊張性亢進による高血圧を示し，その血管平滑筋ではCa2＋スパークの発生が障害されていた。したがって，TRIC-Aチャネルは血管平滑筋でリアノジン受容体によるCa2＋放出を促進し，血圧レベルの設定に寄与する。また，TRIC-A遺伝子近傍の一塩基多型がヒト高血圧のリスク因子となり，降圧薬の薬理作用を規定することも示され，TRIC-A多型解析が高血圧の個別化医療において有用な分子診断となることも期待される。

　TRIC channel subtypes form bullet-shaped homo-trimeric assemblies and behave as K＋ channels in intracellular membrane systems. The pathophysiological defects observed in knockout mice suggest that TRIC channels mediate counter-K＋ movements to facilitate Ca2＋ release from intracellular stores in various cell types. In vascular smooth muscle cells（VSMCs），Ca2＋ release mediated by ryanodine receptors（RyRs）generates local Ca2＋ sparks, which activate cell-surface Ca2＋-dependent K＋ channels and induce hyperpolarization. Tric-a-knockout mice develop hypertension due to elevated resting tonus in the mutant VSMCs. In Tric-a-knockout VSMCs, RyR-mediated Ca2＋ sparks are compromised and the hyperpolarization signaling is thus impaired. Under such depolarized conditions, voltage-dependent L-type Ca2＋ channels are hyper-activated to enhance resting tonus in Tric-a-knockout VSMCs. Therefore, the expression level of TRIC-A channels in VSMCs seems to set resting blood pressure at whole animal level. Moreover, our association study identified several single nucleotide polymorphisms（SNPs）around the TRIC-A gene that increase a hypertension risk and restrict the efficiency of antihypertensive drugs. The observations suggest that the TRIC-A SNPs can provide biomarkers for the diagnosis and personalized medical treatment of essential hypertension.