Sigma receptor

The sigma receptors σ1 and σ2 bind to ligands such as 4-PPBP (4-phenyl-1-(4-phenylbutyl) piperidine),[1] SA 4503 (cutamesine), ditolylguanidine, dimethyltryptamine,[2] and siramesine.[3] They are named by pharmacological similarities, and are evolutionarily unrelated.

ERG2/Sigma-1 receptor
OPM superfamily446
OPM protein5hk1
Sigma intracellular receptor 2

The fungal protein ERG2, a C-8 sterol isomerase, falls into the same protein family as sigma-1. Both localize to the ER membrane, although sigma-1 is also reported to be a cell surface receptor. Sigma-2 is an EXPREA domain protein with a mostly intracellular (ER membrane) localization.


σ–receptors were once thought to be a type of opioid receptor, even though such drugs had no clinically relevant affinities for μ (mu), κ (kappa), or δ (delta) receptors.[4]

However, pharmacological testing indicated that the σ-receptors were activated by drugs completely unrelated to the opioids, and their function was unrelated to the function of the opioid receptors. For example, phencyclidine (PCP), and the antipsychotic haloperidol may interact with σ-receptors as biased agonists/antagonists at sigma 1 (versus sigma 2.) Neither phencyclidine nor haloperidol have any appreciable chemical similarity to the opioids.

When the σ1 receptor was isolated and cloned, it was found to have no structural similarity to the opioid receptors. At this point, they were designated as a separate class of receptors.


The function of these receptors is poorly understood.[5] Activation of σ–receptors by an agonist ligand may induce hallucinogenic effects and also may be responsible for the paradoxical convulsions sometimes seen in opiate overdose. Drugs known to be σ–agonists include cocaine, morphine/diacetylmorphine, opipramol, PCP, fluvoxamine, methamphetamine, dextromethorphan, and the herbal antidepressant berberine. However the exact role of σ–receptors is difficult to establish as many σ–agonists also bind to other targets such as the κ-opioid receptor and the NMDA glutamate receptor. In animal experiments, σ–antagonists such as rimcazole were able to block convulsions from cocaine overdose. σ–antagonists are also under investigation for use as antipsychotic medications.

The abundant neurosteroid steroid hormone DHEA is an agonist at sigma receptors and along with pregnenolone could be endogenous agonist ligands; opposed by sigma antagonistic activity from progesterone.[6] Another endogenous ligand, N,N-dimethyltryptamine, was also found to interact with σ1.[7][8]

Physiologic effectsEdit

Physiologic effects when the σ–receptor is activated include hypertonia, tachycardia, tachypnea, antitussive effects, and mydriasis. Some σ–receptor agonists—such as cocaine, a weak σ–agonist—exert convulsant effects in animals. Behavioral reactions to σ–agonists are rather heterogeneous: some individuals find σ–receptor agonists euphoric with significant anti-depressive effects. Other individuals, however, experience dysphoria and often report feelings of malaise or anxiety.[citation needed]

In 2007 selective σ–receptor agonists were shown to produce antidepressant-like effects in mice.[9]





  1. ^ Yang S, Bhardwaj A, Cheng J, Alkayed NJ, Hurn PD, Kirsch JR (May 2007). "Sigma receptor agonists provide neuroprotection in vitro by preserving bcl-2". Anesthesia and Analgesia. 104 (5): 1179–84, tables of contents. doi:10.1213/01.ane.0000260267.71185.73. PMC 2596726. PMID 17456670.
  2. ^ Fontanilla D, Johannessen M, Hajipour AR, Cozzi NV, Jackson MB, Ruoho AE (February 2009). "The hallucinogen N,N-dimethyltryptamine (DMT) is an endogenous sigma-1 receptor regulator". Science. 323 (5916): 934–7. Bibcode:2009Sci...323..934F. doi:10.1126/science.1166127. PMC 2947205. PMID 19213917.
  3. ^ Skuza G, Rogóz Z (June 2006). "The synergistic effect of selective sigma receptor agonists and uncompetitive NMDA receptor antagonists in the forced swim test in rats". Journal of Physiology and Pharmacology. 57 (2): 217–29. PMID 16845227.
  4. ^ Su, TP; Su, TC; Nakamura, Y (Apr 2016). "The Sigma-1 Receptor as a Pluripotent Modulator in Living Systems". Trends in Pharmacological Sciences. 37 (4): 262–278. doi:10.1016/ PMC 4811735. PMID 26869505.
  5. ^ Leonard BE (November 2004). "Sigma receptors and sigma ligands: background to a pharmacological enigma". Pharmacopsychiatry. 37 Suppl 3: S166–70. doi:10.1055/s-2004-832674. PMID 15547782.
  6. ^ a b Maurice T, Su TP (November 2009). "The pharmacology of sigma-1 receptors". Pharmacology & Therapeutics. 124 (2): 195–206. doi:10.1016/j.pharmthera.2009.07.001. PMC 2785038. PMID 19619582.
  7. ^ Guitart X, Codony X, Monroy X (July 2004). "Sigma receptors: biology and therapeutic potential". Psychopharmacology. 174 (3): 301–19. doi:10.1007/s00213-004-1920-9. PMID 15197533.
  8. ^ Fontanilla D, Johannessen M, Hajipour AR, Cozzi NV, Jackson MB, Ruoho AE (February 2009). "The hallucinogen N,N-dimethyltryptamine (DMT) is an endogenous sigma-1 receptor regulator". Science. 323 (5916): 934–7. Bibcode:2009Sci...323..934F. doi:10.1126/science.1166127. PMC 2947205. PMID 19213917.
  9. ^ Wang J, Mack AL, Coop A, Matsumoto RR (November 2007). "Novel sigma (sigma) receptor agonists produce antidepressant-like effects in mice". European Neuropsychopharmacology. 17 (11): 708–16. doi:10.1016/j.euroneuro.2007.02.007. PMC 4041597. PMID 17376658.
  10. ^ "(ACMD) Methoxetamine Report (2012)" (PDF). UK Home Office. 2012-10-18. p. 14. Retrieved 2012-10-22.
  11. ^ Vollenweider FX, Leenders KL, Oye I, Hell D, Angst J (February 1997). "Differential psychopathology and patterns of cerebral glucose utilisation produced by (S)- and (R)-ketamine in healthy volunteers using positron emission tomography (PET)". European Neuropsychopharmacology. 7 (1): 25–38. doi:10.1016/S0924-977X(96)00042-9. PMID 9088882.
  12. ^ Klepstad P, Maurset A, Moberg ER, Oye I (October 1990). "Evidence of a role for NMDA receptors in pain perception". European Journal of Pharmacology. 187 (3): 513–8. doi:10.1016/0014-2999(90)90379-k. PMID 1963598.
  13. ^ Calabrese JR, Suppes T, Bowden CL, Sachs GS, Swann AC, McElroy SL, Kusumakar V, Ascher JA, Earl NL, Greene PL, Monaghan ET (November 2000). "A double-blind, placebo-controlled, prophylaxis study of lamotrigine in rapid-cycling bipolar disorder. Lamictal 614 Study Group". The Journal of Clinical Psychiatry. 61 (11): 841–50. doi:10.4088/jcp.v61n1106. PMID 11105737.
  14. ^ Ng F, Hallam K, Lucas N, Berk M (August 2007). "The role of lamotrigine in the management of bipolar disorder". Neuropsychiatric Disease and Treatment. 3 (4): 463–74. PMC 2655087. PMID 19300575.
  15. ^ Peeters M, Romieu P, Maurice T, Su TP, Maloteaux JM, Hermans E (April 2004). "Involvement of the sigma 1 receptor in the modulation of dopaminergic transmission by amantadine". The European Journal of Neuroscience. 19 (8): 2212–20. doi:10.1111/j.0953-816X.2004.03297.x. PMID 15090047.
  16. ^ Zhang CL, Feng ZJ, Liu Y, Ji XH, Peng JY, Zhang XH, Zhen XC, Li BM (2012). "Methylphenidate enhances NMDA-receptor response in medial prefrontal cortex via sigma-1 receptor: a novel mechanism for methylphenidate action". PLOS ONE. 7 (12): e51910. Bibcode:2012PLoSO...751910Z. doi:10.1371/journal.pone.0051910. PMC 3527396. PMID 23284812.
  17. ^ Kamei J (Oct–Dec 1996). "Role of opioidergic and serotonergic mechanisms in cough and antitussives". Pulmonary Pharmacology. 9 (5–6): 349–56. doi:10.1006/pulp.1996.0046. PMID 9232674.
  18. ^ Xu YT, Kaushal N, Shaikh J, Wilson LL, Mésangeau C, McCurdy CR, Matsumoto RR (May 2010). "A novel substituted piperazine, CM156, attenuates the stimulant and toxic effects of cocaine in mice". The Journal of Pharmacology and Experimental Therapeutics. 333 (2): 491–500. doi:10.1124/jpet.109.161398. PMC 2872963. PMID 20100904.
  19. ^

External linksEdit