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[4] with a mostly intracellular (ER membrane) localization.[5]
Classificationedit
Because the σ-receptor was originally discovered to be agonized by benzomorphanopioids and antagonized by naltrexone, σ-receptors were originally believed to be a type of opioid receptor.[6] When the σ1 receptor was isolated and cloned, it was found to have no structural similarity to the opioid receptors, but rather showed similarity to fungal proteins involved in sterol synthesis.[7] At this point, they were designated as a separate class of proteins.
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.[9] Another endogenous ligand, N,N-dimethyltryptamine, was also found to interact with σ1.[10][11]
Physiologic effectsedit
Physiologic effects when the σ-receptor is activated include hypertonia, tachycardia, tachypnea, antitussive effects, and mydriasis.[citation needed] Some σ-receptor agonists—such as cocaine, a weak σ-agonist—exert convulsant effects in animals.
In 2007, selective σ-receptor agonists were shown to produce antidepressant-like effects in mice.[12]
σ-receptors were also shown to have a role in the regulation of iron/heme homeostasis.[13]
^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. PMC2596726. PMID 17456670.
^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. PMC2947205. PMID 19213917.
^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.
^Sanchez-Pulido L, Ponting CP (2014). "TM6SF2 and MAC30, new enzyme homologs in sterol metabolism and common metabolic disease". Frontiers in Genetics. 5: 439. doi:10.3389/fgene.2014.00439. PMC4263179. PMID 25566323.
^Bartz F, Kern L, Erz D, Zhu M, Gilbert D, Meinhof T, Wirkner U, Erfle H, Muckenthaler M, Pepperkok R, Runz H (July 2009). "Identification of Cholesterol-Regulating Genes by Targeted RNAi Screening". Cell Metabolism. 10 (1): 63–75. doi:10.1016/j.cmet.2009.05.009. PMID 19583955.
^Kim FJ, Pasternak GW (2017). "Introduction to Sigma Proteins: Evolution of the Concept of Sigma Receptors". Sigma Proteins: Evolution of the Concept of Sigma Receptors. Handbook of Experimental Pharmacology. Vol. 244. Cham: Springer International Publishing. pp. 1–11. doi:10.1007/164_2017_41. ISBN 978-3-319-65853-7. PMID 28871306.
^Hanner M, Moebius FF, Flandorfer A, Knaus HG, Striessnig J, Kempner E, Glossmann H (July 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. Bibcode:1996PNAS...93.8072H. doi:10.1073/pnas.93.15.8072. PMC38877. PMID 8755605.
^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. S2CID 38914893.
^ abMaurice 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. PMC2785038. PMID 19619582.
^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. PMC2947205. PMID 19213917.
^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. PMC4041597. PMID 17376658.
^Nguyen NT, Jaramillo-Martinez V, Mathew M, Suresh VV, Sivaprakasam S, Bhutia YD, Ganapathy V (January 2023). "Sigma Receptors: Novel Regulators of Iron/Heme Homeostasis and Ferroptosis". International Journal of Molecular Sciences. 24 (19): 14672. doi:10.3390/ijms241914672. ISSN 1422-0067. PMC10572259. PMID 37834119.
^"Researchers identify long-sought activator of sigma receptors in human cells". 2019-01-14. Retrieved 2022-03-14.
^"(ACMD) Methoxetamine Report (2012)" (PDF). UK Home Office. 2012-10-18. p. 14. Retrieved 2012-10-22.
^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. S2CID 26861697.
^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.
^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. S2CID 71423264.
^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. PMC2655087. PMID 19300575.
^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. S2CID 19479968.
^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. PMC3527396. PMID 23284812.
^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.
^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. PMC2872963. PMID 20100904.
^Krutetskaya ZI, Melnitskaya AV, Antonov VG, Nozdrachev AD (May 2019). "Sigma-1 Receptor Antagonists Haloperidol and Chlorpromazine Modulate the Effect of Glutoxim on Na+ Transport in Frog Skin". Doklady. Biochemistry and Biophysics. 484 (1): 63–65. doi:10.1134/S1607672919010186. PMID 31012016. S2CID 126409347.