Functional communication between IP 3 R and STIM2 at subthreshold stimuli is a critical checkpoint for initiation of SOCE

Abstract

Significance STIM proteins sense decreases in [Ca 2+ ] ER and cluster in endoplasmic reticulum (ER)–plasma membrane (PM) junctions where they recruit and activate Orai1. While STIM1 clustering requires substantial [Ca 2+ ] ER decrease, STIM2 displays preclustering under resting conditions and regulates basal Ca 2+ entry. The mechanism(s) underlying constitutive clustering of STIM2 is not known. We show herein that endogenous STIM2 assembles as mobile and immobile clusters and that Orai1 is recruited to the latter. Anchoring of STIM2 clusters is triggered by decreases in local [Ca 2+ ] ER that are mediated by ambient activity of IP 3 R and sensed by the STIM2 N terminus. This functional link between IP 3 R and STIM2 governs constitutive STIM2 clustering and ensures coupling of [Ca 2+ ] ER decrease at subthreshold stimuli with activation of Ca 2+ entry.