TRIC-A shapes oscillatory Ca2+ signals by interaction with STIM1/Orai1 complexes

Abstract

Trimeric intracellular cation (TRIC) channels have been proposed to modulate Ca²⁺ release from the endoplasmic reticulum (ER) and determine oscillatory Ca²⁺ signals. Here, we report that TRIC-A–mediated amplitude and frequency modulation of ryanodine receptor 2 (RyR2)-mediated Ca²⁺ oscillations and inositol 1,4,5-triphosphate receptor (IP₃R)-induced cytosolic signals is based on attenuating store-operated Ca²⁺ entry (SOCE). Further, TRIC-A–dependent delay in ER Ca²⁺ store refilling contributes to shaping the pattern of Ca²⁺ oscillations. Upon ER Ca²⁺ depletion, TRIC-A clusters with stromal interaction molecule 1 (STIM1) and Ca²⁺-release–activated Ca²⁺ channel 1 (Orai1) within ER–plasma membrane (PM) junctions and impairs assembly of the STIM1/Orai1 complex, causing a decrease in Orai1-mediated Ca²⁺ current and SOCE. Together, our findings demonstrate that TRIC-A is a negative regulator of STIM1/Orai1 function. Thus, aberrant SOCE could contribute to muscle disorders associated with loss of TRIC-A.