Sigma-1 receptor

The sigma-1 receptor is a transmembrane protein expressed in many different tissue types. It is particularly concentrated in certain regions of the central nervous system.^[1] It has been implicated in myriad phenomena, including cardiovascular function, schizophrenia, clinical depression, the effects of cocaine abuse, and cancer.^[2][3] Furthermore, although much is known about the binding affinity of hundreds of compounds to the sigma-1 receptor, an endogenous ligand has never been conclusively identified.

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Characteristics

The sigma-1 receptor is defined by its unique pharmacological profile. In 1976 Martin reported that the effects of N-allyl-normetazocine (SKF-10,047) could not be due to μ and κ receptors and a new type of opioid receptor was proposed.^[4] However, ligands to this new “opioid” receptor could not be blocked by opioid antagonists naloxone and naltrexone. Consequently, the opioid classification was eventually dropped and the receptor was later termed the sigma-1 receptor. It was found to have affinity for a number of specific stereoisomers (e.g., (+)-pentazocine and (+)-cyclazocine), a diverse group of psychoactive chemicals such as haloperidol and cocaine, and neurosteroids like progesterone.^[5]

Structure

The sigma-1 receptor is an integeral membrane protein with 223 amino acids. Interestingly, it does not bear a resemblance to any other known mammalian protein. It does, however, share 30% identity and 66% homology with fungal sterol isomerase, while at the same time lacking sterol isomerase enzymatic activity.^[5] Hydropathy analysis of the sigma-1 receptor indicates three hydrophobic regions, with some evidence for two transmembrane segments. A crystal structure of the sigma-1 receptor is unavailable.

Functions

A variety of specific physiological functions have been attributed to the sigma-1 receptor. Chief among these are modulation of Ca²⁺ release, modulation of cardiac myocyte contractility, and inhibition of voltage gated K⁺ channels.^[6] The reasons for these effects are not well understood, even though sigma-1 receptors have been linked circumstantially to a wide variety of signal transduction pathways. Links between sigma-1 receptors and G-proteins have been suggested, but there is also some evidence against this hypothesis.^[7] The sigma-1 receptor has been shown to appear in a complex with voltage gated K⁺ channels (K_v 1.4 and K_v 1.5), leading to the idea that sigma-1 receptors are auxiliary subunits.^[8] Sigma-1 receptors apparently co-localize with IP₃ receptors on the endoplasmic reticulum.^[9] Also, sigma-1 receptors have been shown to appear in galactoceramide enriched domains at the endoplasmic reticulum of mature oligodendrocytes.^[10] The wide scope and effect of ligand binding on sigma-1 receptors has led some to believe that sigma-1 receptors are intracellular signal transduction amplifiers.^[5]

Knockout mice

Sigma-1 receptor knockout mice were created recently. Strangely, the mice demonstrated no overt phenotype.^[11] As expected, however, they did lack locomotor response to the sigma ligand (+)-SKF-100,047 and displayed reduced response to formalin induced pain. Speculation has focused on the ability of other receptors in the sigma family (e.g., sigma-2, with similar binding properties) to compensate for the lack of sigma-1 receptor.^[11]

References