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. 2021 Sep 30;15:685201. doi: 10.3389/fncel.2021.685201

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Copyright © 2021 Shi, Chen, Chen, Yang, Yue, Zhang and Chen.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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Molecular mechanisms of sigma-1 receptor in modulation of mitochondrial function and intracellular calcium homeostasis. Upon the ER stress or agonist stimulation, sigma-1 receptor (Sig-1R) dissociates from binding immunoglobulin protein (BiP) and binds to type 3 inositol 1,4,5-trisphosphate receptor (IP3R3), mainly resides at the mitochondria-associated membranes (MAMs). IP3R3s forms a tripartite complex with voltage-dependent anion-selective channel (VDAC) and glucose-regulated protein 75 (GRP75) to connect the ER and the mitochondria. Sig-1R activation facilitates calcium transfer from endoplasmic reticulum (ER) to mitochondria through IP3R3-GRP75-VDAC1 channel. Excessive ROS production promotes mitochondrial permeability transition pore (MPTP) opening, leading to release of cytochrome c from mitochondria to cytosol. Sig-1R may directly form a complex with IP3R, Bcl-2 and Ras-related C3 botulinum toxin substrate 1 (Rac1). Furthermore, Sig-1R can translocate from MAMs to plasma membrane where it directly or indirectly modulates intracellular calcium homeostasis by regulating activities of various plasma membrane elements including N-methyl-D-aspartate receptors (NMDARs), voltage-gated calcium channels (VGCCs), acid-sensing ion channel a (ASIC1a) and stromal interaction molecules 1 (STIM1)/Orai1 complex.