title: Understanding the molecular mechanism of sigma-1 receptors: towards a hypothesis that sigma-1 receptors are intracellular amplifiers for signal transduction.
abstract: Although sigma receptors were discovered in 1982, the biochemical and physiological roles of sigma receptors have just begun to unveil. Sigma receptors are non-opioid, non-phencyclidine receptors that contain two subtypes: sigma-1 and sigma-2 receptors. The sigma-1 receptor has been cloned and its sequence does not resemble that of any mammalian protein. Sigma-2 receptors have not been cloned. The focus of this review will be on sigma-1 receptors. Sigma-1 receptors contain 223 amino acids and reside primarily at the endoplasmic reticulum. Sigma-1 receptors exist mainly in the central nervous system, but also in the periphery. Sigma-1 receptor ligands include cocaine, (+)-benzomorphans like (+)-pentazocine and (+)N-allyl-normetazocine (or (+)-SKF-10047), and endogenous neurosteroids like progesterone and pregnenolone sulfate. Many pharmacological and physiological actions have been attributed to sigma-1 receptors. These include the regulation of IP3 receptors and calcium signaling at the endoplasmic reticulum, mobilization of cytoskeletal adaptor proteins, modulation of nerve growth factor-induced neurite sprouting, modulation of neurotransmitter release and neuronal firing, modulation of potassium channels as a regulatory subunit, alteration of psychostimulant-induced gene expression, and blockade of spreading depression. Behaviorally, sigma-1 receptors are involved in learning and memory, psychostimulant-induced sensitization, cocaine-induced conditioned place preference, and pain perception. Notably, in almost all the aforementioned biochemical and behavioral tests, sigma-1 agonists, while having no effects by themselves, caused the amplification of signal transductions incurred upon the stimulation of the glutamatergic, dopaminergic, IP3-related metabotropic, or nerve growth factor-related systems. Thus, it is hypothesized that sigma-1 receptors, at least in part, are intracellular amplifiers creating a supersensitized state for signal transduction in the biological system.
authors.affiliation: Cellular Pathobiology Unit, Cellular Neurobiology Research Branch, Intramural Research Program, National Institute on Drug Abuse, NIH, DHHS, 5500 Nathan Shock Drive, MD 21224, Baltimore, USA. TSU@intra.nida.nih.gov
authors.forename: Tsung-Ping
authors.initials: TP
authors.lastname: Su
authors.forename: Teruo
authors.initials: T
authors.lastname: Hayashi
mesh_terms: D000818:Animals; D049673:History, 20th Century; D049674:History, 21st Century; D006801:Humans; D007473:Ion Channels / Q000378:metabolism; D016202:N-Methylaspartate / Q000378:metabolism; D017480:Receptors, sigma / Q000266:history / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D000097605:Sigma-1 Receptor
chemical_list: D007473:Ion Channels; D016202:N-Methylaspartate; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor