Sigma-1 receptor

Sigma-1 receptor

Sigma non-opioid intracellular receptor 1
Symbols  ; ALS16; OPRS1; SR-BP1; SRBP
External IDs ChEMBL: GeneCards:
Species Human Mouse
RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)
PubMed search

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 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 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] However, ligands acting at this new “opioid” receptor were not blocked by the classical opioid antagonists naloxone and naltrexone. Consequently, the opioid classification was eventually dropped and the receptor was later termed the σ1 receptor. It was found to have affinity for the (+)-stereoisomers of several benzomorphans (e.g., (+)-pentazocine and (+)-cyclazocine), various structurally and pharmacologically distinct psychoactive chemicals such as haloperidol and cocaine, and neuroactive steroids like progesterone.[9]


The mammalian σ1 receptor was purified with the aid of radiolabelled pentazocine and azidopamil as reversible and photo affinity probes, respectively, from guinea pig liver, cloned and expressed.[10] The receptor is an integral membrane protein with 223 amino acids. 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 is unavailable.


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.[12] 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,[13] there is also, however, some evidence against a G-protein coupled hypothesis.[14] 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.[15] σ1 receptors apparently co-localize with IP3 receptors on the endoplasmic reticulum.[16] Also, σ1 receptors have been shown to appear in galactoceramide enriched domains at the endoplasmic reticulum of mature oligodendrocytes.[17] 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.[18] 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.[18]


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



  • 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[19]



  • 4-IPBS
  • NE-100
  • L-687,384
  • PD 144418
  • SA-4503
  • spipethiane
  • RHL-033
  • S1RA
  • 3-[[1-[(4-chlorophenyl)methyl]-4-piperidyl]methyl]-1,3-benzoxazol-2-one: very high affinity and subtype selectivity[21]
  • 1'-[(4-fluorophenyl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine][22]
  • 1'-benzyl-6-methoxy-1-phenyl-spiro[6H-furo[3,4-c]pyrazole-4,4'-piperidine][23]
  • (−)-(S)-4-methyl-1-[2-(4-chlorophenoxy)-1-methylethyl]piperidine[24]

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.[25][26]

See also


  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.  
  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.  
  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.  
  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.  
  5. ^ Guitart X, Codony X, Monroy X (2004). "Sigma receptors: biology and therapeutic potential". Psychopharmacology (Berl.) 174 (3): 301–19.  
  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.  
  7. ^ Fontanilla et al.; Jessett, DM; Brown, CG; Radley, DE; Jackson, M. B.; Ruoho, A. E. (2009). "The Hallucinogen N,N-Dimethyltryptamine (DMT) Is an Endogenous Sigma-1 Receptor Regulator". Science 323 (5916): 934–937.  
  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.  
  9. ^ a b 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.  
  10. ^ Hanner M, Moebius FF, Flandorfer A, Knaus HG, Striessnig J, Kempner E, Glossmann H (1996). "Purification, molecular cloning, and expression of the mammalian sigma1-binding site". Proc. Natl. Acad. Sci. U.S.A. 93 (15): 8072–7.  
  11. ^ Moebius FF, Striessnig J, Glossmann H (1997). "The mysteries of sigma receptors: new family members reveal a role in cholesterol synthesis". Trends Pharmacol. Sci. 18 (3): 67–70.  
  12. ^ 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.  
  13. ^ Brimson, James; CA Brown and ST Safrany (12 April 2011). "Antagonists show GTP-sensitive high affinity binding to the sigma-1 receptor". British Journal of Pharmacology 164 (2b): 772–780.  
  14. ^ 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.  
  15. ^ 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 (3): 527–39.  
  16. ^ Hayashi T, Su TP (2001). "Regulating ankyrin dynamics: Roles of sigma-1 receptors". Proc. Natl. Acad. Sci. U.S.A. 98 (2): 491–6.  
  17. ^ 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.  
  18. ^ 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.  
  19. ^ 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.  
  20. ^ Zvejniece, L; Vavers, E; Svalbe, B; Vilskersts, R; Domracheva, I; Vorona, M; Veinberg, G; Misane, I; Stonans, I; Kalvinsh, I; Dambrova, M (2014). "The cognition-enhancing activity of E1R, a novel positive allosteric modulator of sigma-1 receptors". British Journal of Pharmacology 171 (3): 761–71.  
  21. ^ 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.  
  22. ^ 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 (10): 3630–41.  
  23. ^ 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.  
  24. ^ 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.  
  25. ^ EP1787679
  26. ^ 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.  

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