Regulation of store-operated calcium entry

TL;DR

This review explains the molecular mechanisms of store-operated calcium entry (SOCE), focusing on the roles of STIM and Orai proteins, and discusses how CRAC channels form and function in cellular calcium regulation.

Contribution

It provides a comprehensive overview of the history, molecular players, and models of SOCE, highlighting recent advances and ongoing debates in the field.

Findings

Identification of key molecular components like STIM and Orai in SOCE

Clarification of the process of CRAC channel formation and clustering

Discussion of models explaining CRAC channel assembly and regulation

Abstract

Plasma membrane calcium influx through ion channels is crucial for many events in cellular physiology. Cell surface stimuli lead to the production of inositol 1,4,5-trisphosphate (IP3), which binds to IP3 receptors in the endoplasmic reticulum (ER) to release calcium pools from the ER lumen. This leads to depletion of ER calcium pools which has been termed store-depletion. Store-depletion leads the dissociation of calcium ions from the EF-hand motif of the ER calcium sensor Stromal Interaction Molecule 1 (STIM1). This leads to a conformational change in STIM1 which helps it to interact with a plasma membrane (PM) at ER:PM junctions. At these ER:PM junctions, STIM1 binds to and activates a calcium channel known as Orai1 to form calcium-release activated calcium (CRAC) channels. Activation of Orai1 leads to calcium influx, known as store-operated calcium entry (SOCE). In addition to Orai1 and STIM1, the homologs of Orai1 and STIM1, such as Orai2/3 and STIM2 also play a crucial role in calcium homeostasis. The influx of calcium through the Orai channel activates a calcium current that has been termed CRAC currents. CRAC channels form multimers and cluster together in large macromolecular assemblies termed puncta. How these CRAC channels form puncta has been contentious since their discovery. In this review, we will outline the history of SOCE, the molecular players involved in this process (Orai and STIM proteins, TRP channels, SOCE-associated regulatory factor etc.), as well as the models that have been proposed to explain this important mechanism in cellular physiology.