Cytosolic Ca2+ prevents the subplasmalemmal clustering of STIM1: an intrinsic mechanism to avoid Ca2+ overload

Abstract

The stromal interacting molecule (STIM1) is pivotal for store-operated Ca2+ entry (SOC). STIM1 proteins sense the Ca2+ concentration within the lumen of the endoplasmic reticulum (ER) via an EF-hand domain. Dissociation of Ca2+ from this domain allows fast oligomerization of STIM1 and the formation of spatially discrete clusters close to the plasma membrane. By lifetime-imaging of STIM1 interaction, the rearrangement of STIM1, ER Ca2+ concentration ([Ca2+]ER) and cytosolic Ca2+ signals ([Ca2+]cyto) we show that [Ca2+]cyto affects the subcellular distribution of STIM1 oligomers and prevents subplasmalemmal STIM clustering, even if the ER is depleted. These data indicate that [Ca2+]cyto, independently of the ER Ca2+ filling state, crucially tunes the formation and disassembly of subplasmalemmal STIM1 clusters, and, thus, protects cells against Ca2+ overload resulting from excessive SOC activity.