Sigma-1 receptor

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The sigma-1 receptor (σ1R), one of two sigma receptor subtypes, is a chaperone protein at the endoplasmic reticulum (ER) that modulates calcium signaling through the IP3 receptor.[1] In humans, the σ1 receptor is encoded by the SIGMAR1 gene.[2][3]

The σ1 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 several 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 σ1 receptor.

An endogenous ligand for the σ1 receptor has yet to be conclusively identified, but tryptaminergic trace amines, as well as neuroactive steroids such as dehydroepiandrosterone (DHEA) and pregnenolone all activate the receptor.[7]


The σ1 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 activity at the μ and κ receptors (named from the first letter of their selective ligands morphine and ketazocine, respectively) and a new type of opioid receptor was proposed; σ (from the first letter of SKF-10,047).[8] Ligands acting at this new “opioid” receptor were blocked by the classical opioid antagonists naloxone and naltrexone. The opioid classification was eventually dropped however resulting from it not possessing the canonical opioid G-protein coupled receptor structure and the receptor was later referred to as simply the σ1 receptor. It was found to have affinity for the (+)-stereoisomers of several benzomorphans (e.g., (+)-pentazocine and (+)-cyclazocine), as well as various structurally and pharmacologically distinct psychoactive chemicals such as haloperidol and cocaine, and neuroactive steroids like progesterone.[9]


The mammalian σ1 receptor is an integral membrane protein with 223 amino acids.[10] It shows no homology to other mammalian proteins but strikingly shares 30% sequence identity and 69% similarity with the ERG2 gene product of yeast, which is a C 8-C7 sterol isomerase in the ergosterol biosynthetic pathway. Hydropathy analysis of the σ1 receptor indicates three hydrophobic regions.[11] A crystal structure of the σ1 receptor was published in 2016.[12]


A variety of specific physiological functions have been attributed to the σ1 receptor. Chief among these are modulation of Ca2+ release, modulation of cardiac myocyte contractility, and inhibition of voltage gated K+ channels.[13] The reasons for these effects are not well understood, even though σ1 receptors have been linked circumstantially to a wide variety of signal transduction pathways. Links between σ1 receptors and G-proteins have been suggested such as σ1 receptor antagonists showing GTP-sensitive high-affinity binding;[14] there is also, however, some evidence against a G-protein coupled hypothesis.[15] The σ1 receptor has been shown to appear in a complex with voltage gated K+ channels (Kv1.4 and Kv1.5), leading to the idea that σ1 receptors are auxiliary subunits.[16] σ1 receptors apparently co-localize with IP3 receptors on the endoplasmic reticulum .[17] where they may be involved in preventing endoplasmic reticulum stress in neurodegenerative diseases [18]. Also, σ1 receptors have been shown to appear in galactoceramide enriched domains at the endoplasmic reticulum of mature oligodendrocytes.[19] The wide scope and effect of ligand binding on σ1 receptors has led some to believe that σ1 receptors are intracellular signal transduction amplifiers.[9]

Knockout mice

σ1 receptor knockout mice were created in 2009 to study the effects of endogenous DMT. Strangely, the mice demonstrated no overt phenotype.[20] As expected, however, they did lack locomotor response to the σ ligand (+)-SKF-10,047 and displayed reduced response to formalin induced pain. Speculation has focused on the ability of other receptors in the σ family (e.g., σ2, with similar binding properties) to compensate for the lack of σ1 receptor.[20]

Clinical significance

Mutations in sigma-1 receptor have been associated with distal spinal muscular atrophy type 2.[21]


The following ligands have high affinity for the σ1 receptor and possess high binding selectivity over the subtype σ2:



  • Sertraline
  • S1RA
  • 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[22]
  • NE-100

Positive allosteric modulators (PAMs):


  • 4-IPBS
  • PD 144418
  • spipethiane
  • RHL-033
  • 3-[[1-[(4-chlorophenyl)methyl]-4-piperidyl]methyl]-1,3-benzoxazol-2-one: very high affinity and subtype selectivity[25]
  • 1'-[(4-fluorophenyl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine][26]
  • 1'-benzyl-6-methoxy-1-phenyl-spiro[6H-furo[3,4-c]pyrazole-4,4'-piperidine][27]
  • (−)-(S)-4-methyl-1-[2-(4-chlorophenoxy)-1-methylethyl]piperidine[28]

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.[29][30]

See also


  1. Hayashi T, Su TP (Nov 2007). "Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca(2+) 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 (Dec 1996). "Cloning and functional expression of the human type 1 sigma receptor (hSigmaR1)". Biochemical and Biophysical Research Communications. 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 (Feb 1998). "Exon-intron structure, analysis of promoter region, and chromosomal localization of the human type 1 sigma receptor gene". Journal of Neurochemistry. 70 (2): 443–51. doi:10.1046/j.1471-4159.1998.70020443.x. PMID 9453537.
  4. Weissman AD, Su TP, Hedreen JC, London ED (Oct 1988). "Sigma receptors in post-mortem human brains". The Journal of Pharmacology and Experimental Therapeutics. 247 (1): 29–33. PMID 2845055.
  5. Guitart X, Codony X, Monroy X (Jul 2004). "Sigma receptors: biology and therapeutic potential". Psychopharmacology. 174 (3): 301–19. doi:10.1007/s00213-004-1920-9. PMID 15197533.
  6. Zhang H, Cuevas J (Jun 2005). "sigma Receptor activation blocks potassium channels and depresses neuroexcitability in rat intracardiac neurons". The Journal of Pharmacology and Experimental Therapeutics. 313 (3): 1387–96. doi:10.1124/jpet.105.084152. PMID 15764734.
  7. Fontanilla D, Johannessen M, Hajipour AR, Cozzi NV, Jackson MB, Ruoho AE (Feb 2009). "The hallucinogen N,N-dimethyltryptamine (DMT) is an endogenous sigma-1 receptor regulator". Science. 323 (5916): 934–7. doi:10.1126/science.1166127. PMC 2947205. PMID 19213917.
  8. Martin WR, Eades CG, Thompson JA, Huppler RE, Gilbert PE (Jun 1976). "The effects of morphine- and nalorphine- like drugs in the nondependent and morphine-dependent chronic spinal dog". The Journal of Pharmacology and Experimental Therapeutics. 197 (3): 517–32. PMID 945347.
  9. 9.0 9.1 Su TP, Hayashi T (Oct 2003). "Understanding the molecular mechanism of sigma-1 receptors: towards a hypothesis that sigma-1 receptors are intracellular amplifiers for signal transduction". Current Medicinal Chemistry. 10 (20): 2073–80. doi:10.2174/0929867033456783. PMID 12871086.
  10. Hanner M, Moebius FF, Flandorfer A, Knaus HG, Striessnig J, Kempner E, Glossmann H (Jul 1996). "Purification, molecular cloning, and expression of the mammalian sigma1-binding site". Proceedings of the National Academy of Sciences of the United States of America. 93 (15): 8072–7. doi:10.1073/pnas.93.15.8072. PMC 38877. PMID 8755605.
  11. Moebius FF, Striessnig J, Glossmann H (Mar 1997). "The mysteries of sigma receptors: new family members reveal a role in cholesterol synthesis". Trends in Pharmacological Sciences. 18 (3): 67–70. doi:10.1016/s0165-6147(96)01037-1. PMID 9133773.
  12. Schmidt H, Zheng S, Gurpinar E, Koehl A, Mangily A, Kruse A (2016). "Crystal structure of the human σ1 receptor". Nature. 532 (7600): 527–530. doi:10.1038/nature17391. PMC 5550834. PMID 27042935.
  13. Monassier L, Bousquet P (Feb 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.
  14. Brimson JM, Brown CA, Safrany ST (Sep 2011). "Antagonists show GTP-sensitive high-affinity binding to the sigma-1 receptor". British Journal of Pharmacology. 164 (2b): 772–80. doi:10.1111/j.1476-5381.2011.01417.x. PMC 3188898. PMID 21486275.
  15. Hong W, Werling LL (Nov 2000). "Evidence that the sigma(1) receptor is not directly coupled to G proteins". European Journal of Pharmacology. 408 (2): 117–25. doi:10.1016/S0014-2999(00)00774-3. PMID 11080517.
  16. Lupardus PJ, Wilke RA, Aydar E, Palmer CP, Chen Y, Ruoho AE, Jackson MB (Aug 2000). "Membrane-delimited coupling between sigma receptors and K+ channels in rat neurohypophysial terminals requires neither G-protein nor ATP". The Journal of Physiology. 526 (3): 527–39. doi:10.1111/j.1469-7793.2000.00527.x. PMC 2270035. PMID 10922005.
  17. Hayashi T, Su TP (Jan 2001). "Regulating ankyrin dynamics: Roles of sigma-1 receptors". Proceedings of the National Academy of Sciences of the United States of America. 98 (2): 491–6. doi:10.1073/pnas.021413698. PMC 14614. PMID 11149946.
  18. Brimson, James M.; Stephen, Safrany; Heider, Qassam; Tencomnao, Tewin (2018). "Dipentylammonium Binds to the Sigma-1 Receptor and Protects Against Glutamate Toxicity, Attenuates Dopamine Toxicity and Potentiates Neurite Outgrowth in Various Cultured Cell Lines". Neurotoxicity Research. 34 (2): 263–272. doi:10.1007/s12640-018-9883-5. PMID 29589276.
  19. Hayashi T, Su TP (Oct 2004). "Sigma-1 receptors at galactosylceramide-enriched lipid microdomains regulate oligodendrocyte differentiation". Proceedings of the National Academy of Sciences of the United States of America. 101 (41): 14949–54. doi:10.1073/pnas.0402890101. PMC 522002. PMID 15466698.
  20. 20.0 20.1 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 (Oct 2003). "Generation and phenotypic analysis of sigma receptor type I (sigma 1) knockout mice". The European Journal of Neuroscience. 18 (8): 2188–96. doi:10.1046/j.1460-9568.2003.02950.x. PMID 14622179.
  21. Li X, Hu Z, Liu L, Xie Y, Zhan Y, Zi X, Wang J, Wu L, Xia K, Tang B, Zhang R (June 2015). "A SIGMAR1 splice-site mutation causes distal hereditary motor neuropathy". Neurology. 84 (24): 2430–7. doi:10.1212/WNL.0000000000001680. PMID 26078401.
  22. Oberdorf C, Schepmann D, Vela JM, Diaz JL, Holenz J, Wünsch B (Oct 2008). "Thiophene bioisosteres of spirocyclic sigma receptor ligands. 1. N-substituted spiro[piperidine-4,4'-thieno[3,2-c]pyrans]". Journal of Medicinal Chemistry. 51 (20): 6531–7. doi:10.1021/jm8007739. PMID 18816044.
  23. Vavers E, Zvejniece L, Veinberg G, Svalbe B, Domracheva I, Vilskersts R, Dambrova M (2015). "Novel positive allosteric modulators of sigma-1 receptor". SpringerPlus. 4: P51. doi:10.1186/2193-1801-4-S1-P51. The R-configuration enantiomers of methylphenylpiracetam are more active positive allosteric modulators of Sigma-1 receptor than S-configuration enantiomers.
  24. Wang Y, Guo L, Jiang H, Zheng L, Zhang A, Zhen X (2016). "Allosteric Modulation of Sigma-1 Receptors Elicits Rapid Antidepressant Activity". CNS Neuroscience & Therapeutics. 22 (5): 368–77. doi:10.1111/cns.12502. PMID 26854125.
  25. Zampieri D, Grazia Mamolo M, Laurini E, Zanette C, Florio C, Collina S, Rossi D, Azzolina O, Vio L (Jan 2009). "Substituted benzo[d]oxazol-2(3H)-one derivatives with preference for the sigma1 binding site". European Journal of Medicinal Chemistry. 44 (1): 124–30. doi:10.1016/j.ejmech.2008.03.011. PMID 18440098.
  26. Grosse Maestrup E, Wiese C, Schepmann D, Hiller A, Fischer S, Scheunemann M, Brust P, Wünsch B (May 2009). "Synthesis of spirocyclic σ1 receptor ligands as potential PET radiotracers, structure-affinity relationships and in vitro metabolic stability". Bioorganic & Medicinal Chemistry. 17 (10): 3630–41. doi:10.1016/j.bmc.2009.03.060. PMID 19394833.
  27. Schläger T, Schepmann D, Würthwein EU, Wünsch B (Mar 2008). "Synthesis and structure-affinity relationships of novel spirocyclic sigma receptor ligands with furopyrazole structure". Bioorganic & Medicinal Chemistry. 16 (6): 2992–3001. doi:10.1016/j.bmc.2007.12.045. PMID 18221879.
  28. Berardi F, Loiodice F, Fracchiolla G, Colabufo NA, Perrone R, Tortorella V (May 2003). "Synthesis of chiral 1-[Ω-(4-chlorophenoxy)alkyl]-4-methylpiperidines and their biological evaluation at σ1, σ2, and sterol Δ8–Δ7 isomerase sites". Journal of Medicinal Chemistry. 46 (11): 2117–24. doi:10.1021/jm021014d. PMID 12747784.
  29. EP1787679
  30. Lee IT, Chen S, Schetz JA (Jan 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". European Journal of Pharmacology. 578 (2–3): 123–36. doi:10.1016/j.ejphar.2007.09.020. PMC 2963108. PMID 17961544.

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