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.