Poster abstracts

Poster number 21 submitted by Xinyu Zhou

TRIC-A prevents store-overload induced calcium release through interaction with the cardiac ryanodine receptor.

Xinyu Zhou (Department of Surgery, Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University), Ki Ho Park, Pei-hui Lin, Mingzhai Sun, Pu Duann (Department of Surgery, Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University), Daiju Yamazaki (Department of Biological Chemistry, Kyoto University Graduate School of Pharmaceutical Sciences, Kyoto, Japan), S.R. Wayne Chen (Departments of Physiology and Pharmacology, and Biochemistry and Molecular Biology, Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Alberta, Canada), Hiroshi Takeshima (Department of Biological Chemistry, Kyoto University Graduate School of Pharmaceutical Sciences, Kyoto, Japan), Jianjie Ma (Department of Surgery, Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University)

Abstract:
TRIC-A and TRIC-B are trimeric intracellular cation channels located at the sarcoplasmic reticulum (SR) or endoplasmic reticulum (ER) of multiple cell types. These channels regulate the permeability of K ions across the SR/ER and consequently the movement of Ca ions during excitation-contraction coupling. Previously we showed that genetic ablation of TRIC led to compromised K-permeability and Ca release across the SR membrane, supporting the hypothesis that TRIC could function as counter-ion channels that allows the flow of K ions into the SR during the acute phase of Ca release. In the absence of TRIC, overload of Ca inside the ER/SR causes instability of Ca storage and release, leading to stress-induced dysfunction of multiple tissues. Spontaneous Ca waves, also called store overload-induced Ca release (SOICR) mediated by the type 2 ryanodine receptor (RyR2), evoke ventricular tachyarrhythmia in individuals with heart failure. Our biochemical studies revealed that the carboxyl-tail domain of TRIC-A could interact with the RyR channel, suggesting the possibility that TRIC-A may directly regulate the Ca release activity. We found that TRIC-A, but not TRIC-B, prevented the appearance of SOICR in HEK293 cells expressing RyR2. Cytosolic Ca measurement by Fura-2 and ER luminal Ca measurement by D1ER revealed that expression of TRIC-A in HEK293 cells could prevent overload of Ca inside the ER by targeting the RyR2 channel function. Such effect was translated into suppression of SOICR. These effects appeared to be specific for TRIC-A, as co-expression of RyR2 with TRIC-B did not affect SOICR. Together, our data suggest that functional interaction between TRIC-A and RyR can modulate the Ca release process from internal stores and regulate Ca homeostasis across the ER/SR.

References:
Yazawa M, Ferrante C, Feng J, et al. TRIC channels are essential for Ca2+ handling in intracellular stores. Nature. 2007;448:78–82.

Yamazaki D, Tabara Y, Kita S, et al. TRIC-A channels in vascular smooth muscle contribute to blood pressure maintenance. Cell Metab. 2011; 14:231–241.

Jiang D, Xiao B, Yang D, Wang R, Choi P, Zhang L, Cheng H, Chen SR. RyR2 mutations linked to ventricular tachycardia and sudden death reduce the threshold for store-overload-induced Ca2+ release (SOICR). Proc Natl Acad Sci. 2004; 101:13062–13067.

Xinyu Zhou, Pei-hui Lin, Daiju Yamazaki, Ki Ho Park, Shinji Komazaki, S.R. Wayne Chen, Hiroshi Takeshima, Jianjie Ma Trimeric Intracellular Cation Channels and Sarcoplasmic/Endoplasmic Reticulum Calcium Homeostasis. Circ Res. 2014; 114: 706-716

Keywords: TRIC, RyR, SOICR