The Sigma-1 Receptor as a Pluripotent Modulator in Living Systems

Abstract

The sigma-1 receptor (Sig-1R) is an endoplasmic reticulum (ER) protein resides specifically at the interface between ER and mitochondria, called the MAM, where the Sig-1R is recently reported to be involved in certain CNS diseases. In addition to being able to translocate to the plasma membrane to interact with ion channels and other receptors, the Sig-1R is found to exist at the nuclear envelope where it recruits chromatin-remodeling factors to affect the transcription of genes. As well, thorough experimental and bioinformatic means, Sig-1Rs are reported to interact with other membranous or soluble proteins at other loci, including the cytosol. We propose that the Sig-1R is a pluripotent modulator with resultant multiple functional manifestations in the living system.

Cocaine engages a non-canonical, dopamine-independent, mechanism that controls neuronal excitability in the nucleus accumbens

“…3f). Although σ1 is an inter-organelle signaling modulator that exerts several distinct functions (e.g., ER lipid metabolisms/transports [60], and indirectly regulating the transcription of genes [4]), these data Right: Sample traces. In (a), one-way ANOVA, ****p < 0.0001.…”

“…Previous studies suggest that activation of the sigma-1 receptor (σ1), an endoplasmic reticulum (ER) chaperone [3] that regulates a variety of proteins through physical protein-protein interactions [4], contributes to addiction processes [5,6]. Consistent with this role, σ1 regulates both DA receptors signaling (DARs) via protein-protein interactions [7,8] and DA release in the striatum [9].…”

A Review of the Human Sigma-1 Receptor Structure

“…Identification of the structural elements and amino acids involved in the large number of reported protein-protein interactions (reviewed in [1]) is required to understand the specificity of S1R signaling. It is possible that the interface for protein-protein interactions is only accessible in the monomeric form [32,62,63], however, the surface-exposed helices A and B are attractive potential sites of interaction based on the trimeric structures.…”

“…Despite its small size S1R acts to regulate the activity of a large number of cellular proteins and is itself regulated by small molecule binding [1]. The reported protein interaction partners include ion channels (both ligand and voltage gated), GPCRs, transcription factors and the endoplasmic reticulum (ER) chaperone protein BiP [2].…”

Sigma-1 receptors control immune-driven peripheral opioid analgesia during inflammation in mice

“…The sigma-1 receptor acts as a ligand-operated chaperone, which modifies the function of several receptors and channels important in neurotransmission (2), and has been the focus of intense preclinical research as a new pharmacological target for pain treatment (3,4). The role of sigma-1 receptors in neuropathic pain has been extensively studied, and it has been widely reported that sigma-1 inhibition decreases central sensitization (3), which plays a key role in this type of pain (5).…”