Sigma-1 receptor



opioid receptor, sigma 1
Identifiers
Symbol OPRS1
Entrez 10280
HUGO 8157
OMIM 601978
RefSeq NM_147157
UniProt Q2TSD1
Other data
Locus Chr. 9 [1]

The sigma-1 receptor is a ligand has never been conclusively identified.

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 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 (Kv 1.4 and Kv 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

  1. ^ Weissman AD, Su TP, Hedreen JC, London ED (1988). "Sigma receptors in post-mortem human brains". J. Pharmacol. Exp. Ther. 247 (1): 29-33. PMID 2845055.
  2. ^ Guitart X, Codony X, Monroy X (2004). "Sigma receptors: biology and therapeutic potential". Psychopharmacology (Berl.) 174 (3): 301-19. doi:10.1007/s00213-004-1920-9. PMID 15197533.
  3. ^ Zhang H, Cuevas J (2005). "sigma Receptor activation blocks potassium channels and depresses neuroexcitability in rat intracardiac neurons". J. Pharmacol. Exp. Ther. 313 (3): 1387-96. doi:10.1124/jpet.105.084152. PMID 15764734.
  4. ^ Martin WR, Eades CG, Thompson JA, Huppler RE, Gilbert PE (1976). "The effects of morphine- and nalorphine- like drugs in the nondependent and morphine-dependent chronic spinal dog". J. Pharmacol. Exp. Ther. 197 (3): 517-32. PMID 945347.
  5. ^ a b c Su TP, Hayashi T (2003). "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 (20): 2073-80. PMID 12871086.
  6. ^ Monassier L, Bousquet P (2002). "Sigma receptors: from discovery to highlights of their implications in the cardiovascular system". Fundamental & clinical pharmacology 16 (1): 1-8. PMID 11903506.
  7. ^ Hong W, Werling LL (2000). "Evidence that the sigma(1) receptor is not directly coupled to G proteins". Eur. J. Pharmacol. 408 (2): 117-25. PMID 11080517.
  8. ^ Lupardus PJ, Wilke RA, Aydar E, Palmer CP, Chen Y, Ruoho AE, Jackson MB (2000). "Membrane-delimited coupling between sigma receptors and K+ channels in rat neurohypophysial terminals requires neither G-protein nor ATP". J. Physiol. (Lond.) 526 Pt 3: 527-39. PMID 10922005.
  9. ^ Hayashi T, Su TP (2001). "Regulating ankyrin dynamics: Roles of sigma-1 receptors". Proc. Natl. Acad. Sci. U.S.A. 98 (2): 491-6. doi:10.1073/pnas.021413698. PMID 11149946.
  10. ^ Hayashi T, Su TP (2004). "Sigma-1 receptors at galactosylceramide-enriched lipid microdomains regulate oligodendrocyte differentiation". Proc. Natl. Acad. Sci. U.S.A. 101 (41): 14949-54. doi:10.1073/pnas.0402890101. PMID 15466698.
  11. ^ a b 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 (2003). "Generation and phenotypic analysis of sigma receptor type I (sigma 1) knockout mice". Eur. J. Neurosci. 18 (8): 2188-96. PMID 14622179.
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Angiotensin - Bradykinin (B1, B2) / Tachykinin (TACR1) - Calcitonin gene-related peptide - Galanin - GPCR neuropeptide (B/W, FF, S, Y) - Neurotensin
 
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