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. HISTORY AND INTRODUCTIONOriginally intending to identify a subtype of opioid receptors, the sigma/opioid receptors as proposed by Martin et al.. [1], Su [2] used the tritiated prototypic sigma/opioid receptor ligand SKF-10047 (N-allyl-normetazocine) in binding assays and identified a protein that has a nanomolar affinity for SKF-10047. Surprisingly though, the protein had no affinity for the opioid antagonist naloxone. This raised a possibility that the protein identified by Su [2] may not be the sigma/opioid receptor proposed by Martin et al..[1] but may represent a new receptor at which SKF-10047 has an affinity. The protein identified by Su [2] was later termed "sigma receptor", with the word "opioid" dropped to differentiate it from the sigma/opioid receptor and the word "sigma" retained for it being identified with the labeled ligand SKF-10047. So far, the sigma/opioid receptor proposed by Martin et al.. has not been clearly identified.The sigma receptor has several peculiarities in its ligand binding profile and its distri...

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