- Sigma-1 receptor
Name=opioid receptor, sigma 1
LocusSupplementaryData=The sigma-1 receptor is a
transmembrane proteinexpressed in many different tissue types. It is particularly concentrated in certain regions of the central nervous system.cite journal | author = Weissman AD, Su TP, Hedreen JC, London ED | title = Sigma receptors in post-mortem human brains | journal = J. Pharmacol. Exp. Ther. | volume = 247 | issue = 1 | pages = 29–33 | year = 1988 | pmid = 2845055 | doi = | issn = ] It has been implicated in myriad phenomena, including cardiovascular function, schizophrenia, clinical depression, the effects of cocaineabuse, and cancer.cite journal | author = Guitart X, Codony X, Monroy X | title = Sigma receptors: biology and therapeutic potential | journal = Psychopharmacology (Berl.) | volume = 174 | issue = 3 | pages = 301–19 | year = 2004 | pmid = 15197533 | doi = 10.1007/s00213-004-1920-9 | issn = ] cite journal | author = Zhang H, Cuevas J | title = sigma Receptor activation blocks potassium channels and depresses neuroexcitability in rat intracardiac neurons | journal = J. Pharmacol. Exp. Ther. | volume = 313 | issue = 3 | pages = 1387–96 | year = 2005 | pmid = 15764734 | doi = 10.1124/jpet.105.084152 | issn = ] 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 receptorwas proposed.cite journal | author = Martin WR, Eades CG, Thompson JA, Huppler RE, Gilbert PE | title = The effects of morphine- and nalorphine- like drugs in the nondependent and morphine-dependent chronic spinal dog | journal = J. Pharmacol. Exp. Ther. | volume = 197 | issue = 3 | pages = 517–32 | year = 1976 | pmid = 945347 | doi = | issn = ] However, ligands to this new “opioid” receptor could not be blocked by opioid antagonists naloxoneand 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 haloperidoland cocaine, and neurosteroids like progesterone.cite journal | author = Su TP, Hayashi T | title = Understanding the molecular mechanism of sigma-1 receptors: towards a hypothesis that sigma-1 receptors are intracellular amplifiers for signal transduction | journal = Curr. Med. Chem. | volume = 10 | issue = 20 | pages = 2073–80 | year = 2003 | pmid = 12871086 | doi = | issn = ]
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. ] Hydropathy analysis of the sigma-1 receptor indicates three hydrophobicregions, 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
myocytecontractility, and inhibition of voltage gated K+ channels.cite journal | author = Monassier L, Bousquet P | title = Sigma receptors: from discovery to highlights of their implications in the cardiovascular system | journal = Fundamental & clinical pharmacology | volume = 16 | issue = 1 | pages = 1–8 | year = 2002 | pmid = 11903506 | doi = | issn = ] 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.cite journal | author = Hong W, Werling LL | title = Evidence that the sigma(1) receptor is not directly coupled to G proteins | journal = Eur. J. Pharmacol. | volume = 408 | issue = 2 | pages = 117–25 | year = 2000 | pmid = 11080517 | doi = | issn = ] 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 subunits.cite journal | author = Lupardus PJ, Wilke RA, Aydar E, Palmer CP, Chen Y, Ruoho AE, Jackson MB | title = Membrane-delimited coupling between sigma receptors and K+ channels in rat neurohypophysial terminals requires neither G-protein nor ATP | journal = J. Physiol. (Lond.) | volume = 526 Pt 3 | issue = | pages = 527–39 | year = 2000 | pmid = 10922005 | doi = | issn = ] Sigma-1 receptors apparently co-localize with IP3 receptors on the endoplasmic reticulum.cite journal | author = Hayashi T, Su TP | title = Regulating ankyrin dynamics: Roles of sigma-1 receptors | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 98 | issue = 2 | pages = 491–6 | year = 2001 | pmid = 11149946 | doi = 10.1073/pnas.021413698 | issn = ] Also, sigma-1 receptors have been shown to appear in galactoceramide enriched domains at the endoplasmic reticulum of mature oligodendrocytes.cite journal | author = Hayashi T, Su TP | title = Sigma-1 receptors at galactosylceramide-enriched lipid microdomains regulate oligodendrocyte differentiation | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 101 | issue = 41 | pages = 14949–54 | year = 2004 | pmid = 15466698 | doi = 10.1073/pnas.0402890101 | issn = ] 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. ]
Sigma-1 receptor knockout mice were created recently. Strangely, the mice demonstrated no overt phenotype.cite journal | author = Langa F, Codony X, Tovar V, Lavado A, Giménez E, Cozar P, Cantero M, Dordal A, Hernández E, Pérez R, Monroy X, Zamanillo D, Guitart X, Montoliu L | title = Generation and phenotypic analysis of sigma receptor type I (sigma 1) knockout mice | journal = Eur. J. Neurosci. | volume = 18 | issue = 8 | pages = 2188–96 | year = 2003 | pmid = 14622179 | doi = | issn = ] 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. ]
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