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. 2022 Aug 20;12(8):1152. doi: 10.3390/biom12081152

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© 2022 by the authors.

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

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Functional communication between IP₃R and STIM2 at subthreshold stimuli is a critical checkpoint for initiation of SOCE. The model refers to cellular responses under ambient and low-intensity stimuli. IP₃R and STIM2 are localized in the ER–PM junctional region. Under ambient conditions (without agonist addition), constitutive PLC-dependent PIP₂ hydrolysis as well as cAMP/PKA activity regulate IP₃R activity. When STIM2 is in the vicinity of a functional IP₃R, it senses the lower [Ca²⁺]_ER (1), which leads to scaffolding to the plasma membrane and immobilization (2). Orai1 is then recruited to immobile STIM2 (3) and with further [Ca²⁺]_ER decrease STIM1 is also recruited to immobile STIM2 (4) [5].