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.
Highlights
Ca2+ signaling plays a central role in cardiac physiology [18]
Trimeric intracellular cation (TRIC) channels have been identified as monovalent cation channels that are located in the endoplasmic reticulum (ER)/sarcoplasmic reticulum (SR) membrane [101, 109]
We further explored the role of TRIC-A in HEK293 cells with inducible expression of ryanodine receptor 2 (RyR2) as a model of store-overload induced Ca2+ release (SOICR) [41, 110]
Summary
Ca2+ signaling plays a central role in cardiac physiology [18]. The regulation of Ca2+ signaling shows a great dynamic range in terms of frequency and spatial-temporal relationship, forming a variety of patterns from localized brief Ca2+ bursts to long-lasting, global Ca2+ transients [8, 17, 18, 53, 68, 81]. The hypothesized interaction of CTT-A and SPRY domain could be a potential target site for therapeutic regulation of RyR activity Together, these data revealed a novel role of TRIC-A as a direct modulator of RyR2, in addition to its counter-ion channel function. These data revealed a novel role of TRIC-A as a direct modulator of RyR2, in addition to its counter-ion channel function Both functions would enhance RyR2-mediated Ca2+ release in cardiac muscle. In addition to supporting the counter current movement associated with intracellular Ca release, TRIC-A can interact with RyR channels to directly or indirectly modulate ER/SR Ca homeostasis and crosstalk with mitochondria
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