TRIC-A Channels in Vascular Smooth Muscle Contribute to Blood Pressure Maintenance

Abstract

TRIC channel subtypes, namely TRIC-A and TRIC-B, are intracellular monovalent cation channels postulated to mediate counter-ion movements facilitating physiological Ca(2+) release from internal stores. Tric-a-knockout mice developed hypertension during the daytime due to enhanced myogenic tone in resistance arteries. There are two Ca(2+) release mechanisms in vascular smooth muscle cells (VSMCs); incidental opening of ryanodine receptors (RyRs) generates local Ca(2+) sparks to induce hyperpolarization, while agonist-induced activation of inositol trisphosphate receptors (IP(3)Rs) evokes global Ca(2+) transients causing contraction. Tric-a gene ablation inhibited RyR-mediated hyperpolarization signaling to stimulate voltage-dependent Ca(2+) influx, and adversely enhanced IP(3)R-mediated Ca(2+) transients by overloading Ca(2+) stores in VSMCs. Moreover, association analysis identified single-nucleotide polymorphisms (SNPs) around the human TRIC-A gene that increase hypertension risk and restrict the efficiency of antihypertensive drugs. Therefore, TRIC-A channels contribute to maintaining blood pressure, while TRIC-A SNPs could provide biomarkers for constitutional diagnosis and personalized medical treatment of essential hypertension.

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

“…Therefore, VSMCs are an ideal model system to examine the physiological functions of TRIC channel subtypes. We recently detected not only insufficient RyR-mediated Ca 2ϩ sparks but also facilitated IP 3 R-mediated Ca 2ϩ transients in Tric-a knock-out VSMCs (15). These observations led to the hypothesis that TRIC-A channels preferentially support RyR-mediated Ca 2ϩ release and also regulate Ca 2ϩ distribution between the caffeine-and IP 3 -sensitive stores.…”

“…Transgenic Mice and Blood Pressure Monitoring-Transgenic mice overexpressing TRIC-A channels under the control of the human ␣-smooth muscle actin promoter were generated and genotyped as previously described (15). The transgenic and wild-type littermates (8 -12 weeks old) were examined physiologically and biochemically in this study.…”

“…Double-knock-out mice lacking both the Tric-a and Tric-b genes show embryonic cardiac failure, and the mutant car-diomyocytes display weak RyR-mediated Ca 2ϩ release from the SR (14). Tric-a knock-out mice develop hypertension associated with vascular hypertonicity, and the mutant vascular smooth muscle cells (VSMCs) show insufficient Ca 2ϩ sparks for inducing hyperpolarization (15). Moreover, mutant skeletal muscle from Tric-a knock-out mice occasionally exhibits alternan contraction responses, likely due to destabilized RyR-mediated Ca 2ϩ release (16).…”

TRIM50 Protein Regulates Vesicular Trafficking for Acid Secretion in Gastric Parietal Cells

“…Briefly, the stomach was removed and turned inside out, and the inverted sac was treated with a Ca 2ϩ -free solution containing 0.025% Pronase E. After the cell debris was removed, the tissue was further digested in a solution containing 1 mM CaCl 2 and 0.05% Pronase E. The separated cells were collected and resuspended in DMEM for loading onto a discontinuous Optiprep (Axis-Shield) gradient composed of solutions with densities of 1.139, 1.095, 1.073, and 1.049 g/ml. After centrifugation at 1,000 ϫ g for 8 min, the cells on the top of each layer were collected for Western blot analysis (17).…”

TRIC-B Mutations Causing Osteogenesis Imperfecta

“…Double-knockout mice lacking both the subtypes die during early embryonic stages, and RyR-mediated Ca 2+ release is weakened in the mutant cardiomyocytes. 4) In Tric-a-knockout mice, the mutant vascular smooth muscle shows poor RyRmediated Ca 2+ sparks, 9,10) and the mutant skeletal muscle exhibits 'alternan' contractile responses which are likely generated due to compromised RyR-mediated Ca 2+ release.…”