Co-Expression of TRIC-A and Cardiac Ryanodine Receptor affects Store-Overload Induced Calcium Release in HEK293 Cells

Abstract

TRIC represents a novel class of 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 ER/SR and consequently the movement of Ca ions during excitation-contraction coupling. Previously we showed that genetic ablation of TRIC-A lead to compromised K-permeability and Ca release across the SR/ER membrane, supporting the hypothesis that TRIC could function as counter-ion channels that provide 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 skeletal and cardiac muscles. Cardiomyocytes isolated from the wild type mice often show spontaneous Ca release during SR Ca overload, also called store-overload induced Ca release (SOICR) that is mediated by the type 2 ryanodine receptor (RyR2). The appearance of SOICR was significantly less frequent in the TRIC-A knockout cardiomyocytes. Biochemical studies revealed that the carboxyl-tail domain of TRIC-A could interact with the RyR channel, supporting the possibility that TRIC-A may directly regulate the Ca release activity. It has been shown that SOICR can be reconstituted in HEK293 cells expressing RyR2. We found that expression of TRIC-A in these RyR2-expressing HEK293 cells could prevent overload of Ca inside the ER and abolish SOICR generation. Together, our data suggest that functional interaction between TRIC-A and RyR can modulate the Ca release process from internal stores.