Sigma-1 receptor
From Wikipedia, the free encyclopedia
|
opioid receptor, sigma 1
|
|
| Identifiers | |
| Symbol | OPRS1 |
| HUGO | 8157 |
| Entrez | 10280 |
| OMIM | 601978 |
| RefSeq | NM_147157 |
| UniProt | Q2TSD1 |
| Other data | |
| Locus | Chr. 9 [1] |
The sigma-1 receptor is a transmembrane protein.
[edit] External links
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 system9. It has been implicated in myriad phenomena, including cardiovascular function, schizophrenia, depression, the effects of cocaine abuse, and cancer8,10. 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.
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 proposed11. However, ligands to this new “opioid” receptor could not be blocked by opioid antagonists naloxone and naltrexone. Consequently, the opioid classification was eventually dropped7 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 progesterone12.
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 activity12. 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.
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+ channels13. 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 hypothesis14. The sigma-1 receptor has been shown to appear in a complex with voltage gated K+ channels (Kv 1.4 and Kv 1.5), leading to the idea that sigma-1 receptors are auxiliary subunits15. Sigma-1 receptors apparently co-localize with the IP3 receptors on the endoplasmic reticulum16. Also, sigma-1 receptors have been shown to appear in galactoceramide enriched domains at the endoplasmic reticulum of mature oligodendrocytes17. 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 amplifiers12.
Sigma-1 receptor knockout mice were created recently. Strangely, the mice demonstrated no overt phenotype18. As expected, however, they did lack locomotor response to the sigma ligand (+)-SKF100047 and displayed reduced response to formalin induced pain19. 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 receptor18.
[edit] References
8. Guitart, X., Codony, X. & Monroy, X. Sigma receptors: biology and therapeutic potential. Psychopharmacology (Berl) 174, 301-319 (2004).
9. Weissman, A. D., Su, T. P., Hedreen, J. C. & London, E. D. Sigma receptors in post-mortem human brains. J. Pharmacol. Exp. Ther. 247, 29-33 (1988).
10. Zhang, H. & Cuevas, J. sigma Receptor activation blocks potassium channels and depresses neuroexcitability in rat intracardiac neurons. J. Pharmacol. Exp. Ther. 313, 1387-1396 (2005).
11. Martin, W. R., Eades, C. G., Thompson, J. A., Huppler, R. E. & Gilbert, P. E. The effects of morphine- and nalorphine- like drugs in the nondependent and morphine-dependent chronic spinal dog. J. Pharmacol. Exp. Ther. 197, 517-532 (1976).
12. Su, T. P. & Hayashi, T. Understanding the molecular mechanism of sigma-1 receptors: towards a hypothesis that sigma-1 receptors are intracellular amplifiers for signal transduction. Curr. Med. Chem. 10, 2073-2080 (2003).
13. Monassier, L. & Bousquet, P. Sigma receptors: from discovery to highlights of their implications in the cardiovascular system. Fundam. Clin. Pharmacol. 16, 1-8 (2002).
14. Hong, W. & Werling, L. L. Evidence that the sigma(1) receptor is not directly coupled to G proteins. Eur. J. Pharmacol. 408, 117-125 (2000).
15. Lupardus, P. J. et al. Membrane-delimited coupling between sigma receptors and K+ channels in rat neurohypophysial terminals requires neither G-protein nor ATP. J. Physiol. 526 Pt 3, 527-539 (2000).
16. Hayashi, T. & Su, T. P. Regulating ankyrin dynamics: Roles of sigma-1 receptors. Proceedings of the National Academy of Sciences 98, 491-496 (2001).
17. Hayashi, T. & Su, T. P. Sigma-1 receptors at galactosylceramide-enriched lipid microdomains regulate oligodendrocyte differentiation. Proc. Natl. Acad. Sci. U. S. A. 101, 14949-14954 (2004).
18. Langa, F. et al. Generation and phenotypic analysis of sigma receptor type I (sigma 1) knockout mice. Eur. J. Neurosci. 18, 2188-2196 (2003).
