The sigma-1 receptor chaperone as an inter-organelle signaling modulator

Abstract

Inter-organelle signaling plays important roles in many physiological functions. Endoplasmic reticulum (ER)-mitochondrion signaling affects intramitochondrial calcium (Ca(2+)) homeostasis and cellular bioenergetics. ER-nucleus signaling attenuates ER stress. ER-plasma membrane signaling regulates cytosolic Ca(2+) homeostasis and ER-mitochondrion-plasma membrane signaling regulates hippocampal dendritic spine formation. Here, we propose that the sigma-1 receptor (Sig-1R), an ER chaperone protein, acts as an inter-organelle signaling modulator. Sig-1Rs normally reside at the ER-mitochondrion contact called the MAM (mitochondrion-associated ER membrane), where Sig-1Rs regulate ER-mitochondrion signaling and ER-nucleus crosstalk. When cells are stimulated by ligands or undergo prolonged stress, Sig-1Rs translocate from the MAM to the ER reticular network and plasmalemma/plasma membrane to regulate a variety of functional proteins, including ion channels, receptors and kinases. Thus, the Sig-1R serves as an inter-organelle signaling modulator locally at the MAM and remotely at the plasmalemma/plasma membrane. Many pharmacological/physiological effects of Sig-1Rs might relate to this unique action of Sig-1Rs.

Fig. 1. Model of the Sig-1R binding site

The Sig-1R ligand binding region, highlighted by the circular area, includes the three predicted hydrophobic domains. The SBDLI (steroid binding domain-like 1) and SBDLII (steroid binding domain like II) regions are so named because of sequence homology to yeast sterol isomerase. Aspartate 188 (D188) in SBDLII has been identified as part of cocaine binding site [22]. Though the exact structure is unknown at this time, the three hydrophobic regions are depicted as alpha helical cylinders.

Fig. 2. The Sig-1R chaperone as an interorganelle signaling modulator

At the ER-mitochondrion interface (the MAM), Sig-1Rs, with the help of Sig-1R agonists, can dissociate themselves from another ER chaperone, BiP, and begin to chaperone conformationally unstable IP3Rs to enhance Ca²⁺ signaling from the ER into mitochondria [4] to increase the production of ATP in the cell through the tricarboxylic acid cycle (TCA) in the mitochondria [98]. Via an as yet unknown mechanism, Sig-1Rs at the MAM can also attenuate reactive oxidative species (ROS) at the ER to cause an increase of Bcl2 gene transcription in the nucleus to protect against cell death. Sig-1Rs attenuating the ROS level at the MAM can also, via interorganelle cross-talk, help maintain the integrity of mitochondria to prevent the release of apoptotic molecule cytochrome c that might otherwise destroy Rac•GTP on the PM, which is essential for formation of dendritic spines in neurons. If stimulated by high concentrations of agonists or impacted by extreme ER stress, Sig-1Rs translocate from the MAM to the plasmalemmal area or PM to bind various ion channels (e.g. Na+, K+, NMDA, ASIC and voltage-regulated chloride channels (VGCC)), receptors (e.g. TkB, D1R and other GPCRs) or kinases (e.g. Src). Please note that as long as those ion channels, receptors, or kinases are conformationally stable (i.e., no mutation or no redox stress imposed on the proteins due to the pathophysiology of diseases), the binding of Sig-1Rs does not affect the normal function of those conformationally correct ion channels, receptors, or kinases because chaperones exert their regulatory work only when the target proteins are “sick” and thus become clients. Many diseases are known to involve protein conformation changes. Thus, Sig-1Rs and associated ligands might represent potential therapeutic avenue for many human protein conformation diseases.