title: Facilitated hyperpolarization signaling in vascular smooth muscle-overexpressing TRIC-A channels.
abstract: 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.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Shengchen
authors.initials: S
authors.lastname: Tao
authors.forename: Daiju
authors.initials: D
authors.lastname: Yamazaki
authors.forename: Shinji
authors.initials: S
authors.lastname: Komazaki
authors.forename: Chengzhu
authors.initials: C
authors.lastname: Zhao
authors.forename: Tsunaki
authors.initials: T
authors.lastname: Iida
authors.forename: Sho
authors.initials: S
authors.lastname: Kakizawa
authors.forename: Yuji
authors.initials: Y
authors.lastname: Imaizumi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takeshima
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D020013:Calcium Signaling / Q000502:physiology*; D015870:Gene Expression; D007473:Ion Channels / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000096:biosynthesis* / Q000235:genetics; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism*
chemical_list: D007473:Ion Channels; D009124:Muscle Proteins; C522221:TRIC-A protein, mouse
keywords: Blood Pressure; Ca2+ Spark; Ca2+-dependent K+ Channel; Calcium Imaging; Calcium Intracellular Release; Inositol 1,4,5-Trisphosphate receptor; Potassium Channels; Ryanodine Receptor; TRIC Channel; Vascular Smooth Muscle Cells