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Review
. 2023 Dec 19:14:1330259.
doi: 10.3389/fphys.2023.1330259. eCollection 2023.

Regulatory mechanisms controlling store-operated calcium entry

Goutham Kodakandla  1 , Askar M Akimzhanov  2 , Darren Boehning  1
Affiliations
Review

Regulatory mechanisms controlling store-operated calcium entry

Goutham Kodakandla et al. Front Physiol. .

Abstract

Calcium influx through plasma membrane 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 (IP3R) in the endoplasmic reticulum (ER) to release calcium pools from the ER lumen. This leads to the depletion of ER calcium pools, which has been termed store depletion. Store depletion leads to 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 the 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 the CRAC current. CRAC channels form multimers and cluster together in large macromolecular assemblies termed "puncta". How 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, as well as the models that have been proposed to explain this critical mechanism in cellular physiology.

Keywords: DHHC21; Orai1; S-acylation; STIM1; calcium; immune diseases; store-operated calcium entry.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
General overview of store-operated calcium entry (SOCE). Agonist stimulation through the PLC-coupled receptors leads to IP3-mediated calcium release which leads to ER calcium store depletion. As a result, calcium dissociates from the EF-hand of STIM1 and leads to its activation. This leads to a conformation change in STIM1 which extends its C-terminus toward plasma membrane where it binds to Orai1 channels and form calcium release-activated calcium (CRAC) channels. CRAC channels promote calcium entry from extracellular milieu into the cells. One subunit of STIM1 dimer is shown here for simplicity.
FIGURE 2
FIGURE 2
STIM1-lipid binding at the plasma membrane: (A) The CRAC channels are stabilized at the ER:PM junctions by a multitude of bindings between different domains of Orai1 and STIM1 with plasma membrane lipids upon store depletion. Orai1 undergoes S-acylation at its C143 residue which shuttles the channels to lipid rafts. The SOAR domain of STIM1 binds to the N-terminus region of Orai1 and leads to activation of Orai1 channels. The cholesterol binding domain (CBD) in the SOAR domain also binds to the cholesterol rich phospholipids in the plasma membrane, which is mediated by I364 residue. The polybasic domain of STIM1 binds to the PI(4,5)P2 phospholipids in the plasma membrane which is mediated by the positively charged amino acids in the C-terminal tail of STIM1. Finally, STIM1 undergoes S-acylation at its C437 residue which is crucial for SOCE. One subunit of STIM1 dimer is shown here for simplicity. (B,C) The AlphaFold structure predictions of the compact (presumably inactive) and extended (presumably active) conformations of STIM1 are shown. The residues on STIM1 that interact with the plasma membrane as well as C437 that undergoes S-acylation are highlighted in (C). In (B,C), the lipid bilayer is represented in light blue. The compact model is the AlphaFold prediction of Uniprot #V5J3L2. The extended model is the AlphaFold prediction of Uniprot #Q13586).
FIGURE 3
FIGURE 3
Mechanism of DHHC enzyme catalysis. DHHC enzymes S-acylate their substrates by a two-step mechanism which involves autoacylation followed by transfer of the acyl group to target protein cysteine residues (substrates). In this cartoon, lipid rafts are indicated in yellow. ACSL = Acyl-CoA synthetase long-chain family members.
FIGURE 4
FIGURE 4
Models proposed to explain CRAC channel assembly in SOCE. (A) Overview of CRAC puncta formation after ER calcium store-depletion. (B) IP3R recruitment to puncta with STIM1 and IP3-mediated local calcium depletion (C) The Orai1 diffusion trap model, and (D) S-acylation of Orai1 and STIM1 and recruitment to lipid rafts. The three models are not necessarily mutually exclusive. See the text for details.
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