TRIC-A regulates intracellular Ca2+ homeostasis in cardiomyocytes

Abstract

Trimeric intracellular cation (TRIC) channels have been identified as monovalent cation channels that are located in the ER/SR membrane. Two isoforms discovered in mammals are TRIC-A (TMEM38a) and TRIC-B (TMEM38b). TRIC-B ubiquitously expresses in all tissues, and TRIC-B^-/- mice is lethal at the neonatal stage. TRIC-A mainly expresses in excitable cells. TRIC-A^-/- mice survive normally but show abnormal SR Ca²⁺ handling in both skeletal and cardiac muscle cells. Importantly, TRIC-A mutations have been identified in human patients with stress-induced arrhythmia. In the past decade, important discoveries have been made to understand the structure and function of TRIC channels, especially its role in regulating intracellular Ca²⁺ homeostasis. In this review article, we focus on the potential roles of TRIC-A in regulating cardiac function, particularly its effects on intracellular Ca²⁺ signaling of cardiomyocytes and discuss the current knowledge gaps.

Keywords: Heart; Mitochondria; Nuclear envelope; RyR.

Fig. 1

Multi-functional role of TRIC-A in regulating Ca²⁺ signaling in cardiomyocytes. (a) TRIC-A channels are predominantly localized to the ER/SR, providing counter-current K⁺ movement (green arrows) for SR charge compensation during RyR₂-mediated Ca²⁺ release (thick red arrows). (b) TRIC-A channels directly interact with RyR₂ through its carboxyl terminal tail to modulate RyR₂ opening status. (c) Association between TRIC-A and STIM1 has been proposed to control store-operated Ca²⁺ entry. (d) TRIC-A is found in the nuclear envelope, while its role in modulation of nuclear Ca²⁺ signaling and gene transcription remains largely unknown. (e) TRIC-A may function to modulate Ca²⁺ signaling crosstalk from SR to mitochondria to match the metabolic demand of myocardial workload under physiologic or pathologic conditions