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Sigma-1 receptor: Wikis


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sigma non-opioid intracellular receptor 1
Symbols SIGMAR1; SRBP; OPRS1; FLJ25585; MGC3851
External IDs OMIM601978 MGI1195268 HomoloGene39965 GeneCards: SIGMAR1 Gene
Species Human Mouse
Entrez 10280 18391
Ensembl ENSG00000147955 ENSMUSG00000036078
UniProt Q99720 O55242
RefSeq (mRNA) NM_005866 NM_011014
RefSeq (protein) NP_005857 NP_035144
Location (UCSC) Chr 9:
34.62 - 34.63 Mb
Chr 4:
41.69 - 41.69 Mb
PubMed search [1] [2]

The sigma-1 receptor is a chaperone protein at the endoplasmatic reticulum (ER) that modulates calcium signaling through the IP3 receptor.[1] In humans, the sigma-1 receptor is encoded by the SIGMAR1 gene.[2][3]

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.[4] It has been implicated in myriad phenomena, including cardiovascular function, schizophrenia, clinical depression, the effects of cocaine abuse, and cancer.[5][6] Much is known about the binding affinity of hundreds of synthetic compounds to the sigma-1 receptor.

The only known endogenous ligand of the sigma-1 receptor is the potent hallucinogen dimethyltryptamine (DMT), though endogenous neuroactive steroids such as dehydroepiandrosterone (DHEA) and pregnenolone can also activate the receptor.[7]



The sigma-1 receptor is defined by its unique pharmacological profile. In 1976 Martin reported that the effects of N-allylnormetazocine (SKF-10,047) could not be due to μ and κ receptors and a new type of opioid receptor was proposed.[8] 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 neuroactive steroids like progesterone.[9]


The sigma-1 receptor is an integral 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.[9] 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+ channels.[10] 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.[11] The sigma-1 receptor has been shown to appear in a complex with voltage gated K+ channels (Kv1.4 and Kv1.5), leading to the idea that sigma-1 receptors are auxiliary subunits.[12] Sigma-1 receptors apparently co-localize with IP3 receptors on the endoplasmic reticulum.[13] Also, sigma-1 receptors have been shown to appear in galactoceramide enriched domains at the endoplasmic reticulum of mature oligodendrocytes.[14] 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.[9]

Knockout mice

Sigma-1 receptor knockout mice were created recently. Strangely, the mice demonstrated no overt phenotype.[15] As expected, however, they did lack locomotor response to the sigma ligand (+)-SKF-10,047 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.[15]


Today, ligands are known which have high affinity for the σ1 receptor and possess high binding selctivity over the subtype σ2.

  • 3-[[1-[(4-chlorophenyl)methyl]-4-piperidyl]methyl]-1,3-benzoxazol-2-one: very high affinity and subtype selectivity[16]
  • 1'-[(4-fluorophenyl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine][17]
  • 1-benzyl-6′-methoxy-6′,7′-dihydrospiro[piperidine-4,4′-thieno[3.2-c]pyran]: putative antagonist, selective against 5-HT1A, 5-HT6, 5-HT7, α1A and α2 adrenergic, and NMDA receptors[18]
  • 1'-benzyl-6-methoxy-1-phenyl-spiro[6H-furo[3,4-c]pyrazole-4,4'-piperidine][19]
  • (−)-(S)-4-methyl-1-[2-(4-chlorophenoxy)-1-methylethyl]piperidine[20]
  • PRE-084: agonist
  • PD 144418

Agents exist that have high σ1 affinity but either lack subtype selectivity or have high affinity at other binding sites, thus being more or less dirty/multifunctional, like haloperidol. Furthermore, there is a wide range of agents with an at least moderate σ1 involvement in their binding profile.[21][22]

External links


  1. ^ Hayashi T, Su TP (2007). "Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca2+ signaling and cell survival.". Cell 131 (3): 596–610. doi:10.1016/j.cell.2007.08.036. PMID 17981125.  
  2. ^ Kekuda R, Prasad PD, Fei YJ, Leibach FH, Ganapathy V (December 1996). "Cloning and functional expression of the human type 1 sigma receptor (hSigmaR1)". Biochem. Biophys. Res. Commun. 229 (2): 553–8. doi:10.1006/bbrc.1996.1842. PMID 8954936.  
  3. ^ Prasad PD, Li HW, Fei YJ, Ganapathy ME, Fujita T, Plumley LH, Yang-Feng TL, Leibach FH, Ganapathy V (February 1998). "Exon-intron structure, analysis of promoter region, and chromosomal localization of the human type 1 sigma receptor gene". J. Neurochem. 70 (2): 443–51. PMID 9453537.  
  4. ^ 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.  
  5. ^ 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.  
  6. ^ 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.  
  7. ^ Fontanilla et al. (2009). "The Hallucinogen N,N-Dimethyltryptamine (DMT) Is an Endogenous Sigma-1 Receptor Regulator". Science 323 (5916): 934–937. doi:10.1126/science.1166127. PMID 1166127.  
  8. ^ 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.  
  9. ^ 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. doi:10.2174/0929867033456783. PMID 12871086.  
  10. ^ 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. doi:10.1046/j.1472-8206.2002.00063.x. PMID 11903506.  
  11. ^ 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. doi:10.1016/S0014-2999(00)00774-3. PMID 11080517.  
  12. ^ 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. doi:10.1111/j.1469-7793.2000.00527.x. PMID 10922005.  
  13. ^ 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.  
  14. ^ 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.  
  15. ^ 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. doi:10.1046/j.1460-9568.2003.02950.x. PMID 14622179.  
  16. ^ Zampieri D, Grazia Mamolo M, Laurini E, et al (January 2009). "Substituted benzo[d]oxazol-2(3H)-one derivatives with preference for the sigma1 binding site". Eur J Med Chem 44 (1): 124–30. doi:10.1016/j.ejmech.2008.03.011. PMID 18440098.  
  17. ^ Große Maestrup E, Wiese C, Schepmann D, et al (April 2009). "Synthesis of spirocyclic sigma(1) receptor ligands as potential PET radiotracers, structure-affinity relationships and in vitro metabolic stability". Bioorg. Med. Chem. 17: 3630. doi:10.1016/j.bmc.2009.03.060. PMID 19394833.  
  18. ^ Oberdorf C, Schepmann D, Vela JM, Diaz JL, Holenz J, Wünsch B (October 2008). "Thiophene bioisosteres of spirocyclic sigma receptor ligands. 1. N-substituted spiro[piperidine-4,4'-thieno[3,2-c]pyrans]". J. Med. Chem. 51 (20): 6531–7. doi:10.1021/jm8007739. PMID 18816044.  
  19. ^ Schläger T, Schepmann D, Würthwein EU, Wünsch B (March 2008). "Synthesis and structure-affinity relationships of novel spirocyclic sigma receptor ligands with furopyrazole structure". Bioorg. Med. Chem. 16 (6): 2992–3001. doi:10.1016/j.bmc.2007.12.045. PMID 18221879.  
  20. ^ Berardi F, Loiodice F, Fracchiolla G, Colabufo NA, Perrone R, Tortorella V (May 2003). "Synthesis of chiral 1-[omega-(4-chlorophenoxy)alkyl]-4-methylpiperidines and their biological evaluation at sigma1, sigma2, and sterol delta8-delta7 isomerase sites". J. Med. Chem. 46 (11): 2117–24. doi:10.1021/jm021014d. PMID 12747784.  
  21. ^ EP1787679
  22. ^ Lee IT, Chen S, Schetz JA (January 2008). "An unambiguous assay for the cloned human sigma1 receptor reveals high affinity interactions with dopamine D4 receptor selective compounds and a distinct structure-affinity relationship for butyrophenones". Eur. J. Pharmacol. 578 (2-3): 123–36. doi:10.1016/j.ejphar.2007.09.020. PMID 17961544.  

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