Sigma receptors [σRs]: biology in normal and diseased states

Abstract

This review compares the biological and physiological function of Sigma receptors [σRs] and their potential therapeutic roles. Sigma receptors are widespread in the central nervous system and across multiple peripheral tissues. σRs consist of sigma receptor one (σ1R) and sigma receptor two (σ2R) and are expressed in numerous regions of the brain. The sigma receptor was originally proposed as a subtype of opioid receptors and was suggested to contribute to the delusions and psychoses induced by benzomorphans such as SKF-10047 and pentazocine. Later studies confirmed that σRs are non-opioid receptors (not an µ opioid receptor) and play a more diverse role in intracellular signaling, apoptosis and metabolic regulation. σ1Rs are intracellular receptors acting as chaperone proteins that modulate Ca2+ signaling through the IP3 receptor. They dynamically translocate inside cells, hence are transmembrane proteins. The σ1R receptor, at the mitochondrial-associated endoplasmic reticulum membrane, is responsible for mitochondrial metabolic regulation and promotes mitochondrial energy depletion and apoptosis. Studies have demonstrated that they play a role as a modulator of ion channels (K+ channels; N-methyl-d-aspartate receptors [NMDAR]; inositol 1,3,5 triphosphate receptors) and regulate lipid transport and metabolism, neuritogenesis, cellular differentiation and myelination in the brain. σ1R modulation of Ca2+ release, modulation of cardiac myocyte contractility and may have links to G-proteins. It has been proposed that σ1Rs are intracellular signal transduction amplifiers. This review of the literature examines the mechanism of action of the σRs, their interaction with neurotransmitters, pharmacology, location and adverse effects mediated through them.

High-throughput screening discovers antifibrotic properties of haloperidol by hindering myofibroblast activation

“…It is a single 25-kDa polypeptide and a chaperone protein immersed in lipid rafts of the ER, where it interacts with mitochondria and the mitochondria-associated ER membrane domain (MAM). Upon activation, Sigmar1 modulates the function of multiple receptors and ion channels, contributing to cellular calcium homeostasis (68). Our docking model shows that haloperidol in its highest-ranked binding pose interacts with all residues in the binding pocket of Sigmar1, including Phe133, Glu172, Leu105, Met93, Leu95, Ile178, Val84, His154, and Val152, in line with previous studies pointing to Glu172 as an essential residue for Sigmar1-haloperidol binding (69,70).…”

Pharmacological Analysis of the Anti-epileptic Mechanisms of Fenfluramine in scn1a Mutant Zebrafish

“…As a result, neuronal inhibition is impaired, which is assumed to cause seizures (Wong et al, 2016). Our data suggest that FA reduces epileptiform activity by stimulating 5-HT 2C and 5-HT 1D receptors, leading to enhanced GABAergic neurotransmission (as proven for 5-HT 2C receptors) (Shen and Andrade, 1998; Higgins et al, 2014), and by a σ 1 -antagonistic action that can reduce the excitatory neurotransmission by modulating NMDA responses (Rousseaux and Greene, 2015). In addition, FA also significantly decreases the NAD brain content that might contribute to its anti-epileptic effects.…”

“…In contrast, treatment with the σ 2 -antagonist (SM 21) did not reduce epileptiform activity in scn1a mutant larvae. This result was somewhat anticipated as most studies underline the role of the σ 2 subtype receptor in cancer-related diseases, rather than in brain-related disorders (Rousseaux and Greene, 2015). …”

“…Of interest, a number of studies demonstrate the role of σ 1 receptors in neurological diseases like epilepsy (Rousseaux and Greene, 2015) and overstimulation of σ 1 receptors has been associated with GLUT-related excitatory effects (via NMDA receptors) (Borlot et al, 2014; Nicita et al, 2014; Rousseaux and Greene, 2015). In addition, blockade of σ 1 receptors was associated directly with anti-epileptiform activity (Matsumoto et al, 2002).…”

Cocaine occupancy of sigma1receptors and dopamine transporters in mice

“…In vitro binding profiles for σ receptors and their ligands are remarkably consistent between tissue types and across species (Lever et al, ; Matsumoto et al, ; Rousseaux and Greene, ; Walker et al, ). Binding parameters have been established in Swiss Webster mouse brain, but relatively little work has been done on other strains.…”