Biology:Sigma receptor

From HandWiki
Short description: Class of cell surface receptors
ERG2/Sigma-1 receptor
Identifiers
SymbolERG2_Sigma1R
PfamPF04622
InterProIPR006716
TCDB8.A.63
OPM superfamily446
OPM protein5hk1
Membranome1025
Sigma intracellular receptor 2
Identifiers
SymbolSigma2
InterProIPR016964

Sigma receptors (σ-receptors) are protein cell surface receptors that bind ligands such as 4-PPBP (4-phenyl-1-(4-phenylbutyl) piperidine),[1] SA 4503 (cutamesine), ditolylguanidine, dimethyltryptamine,[2] and siramesine.[3] There are two subtypes, sigma-1 receptors (σ1) and sigma-2 receptors (σ2), which are classified as sigma receptors for their pharmacological similarities, even though they are evolutionarily unrelated.

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]

Classification

Because the σ-receptor was originally discovered to be agonized by benzomorphan opioids 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.

Function

The function of these receptors is poorly understood.[8] Drugs known to be σ-agonists include cocaine, morphine/diacetylmorphine, opipramol, PCP, fluvoxamine, methamphetamine, dextromethorphan, and berberine.[citation needed] 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.[9] Another endogenous ligand, N,N-dimethyltryptamine, was also found to interact with σ1.[10][11]

Physiologic effects

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]

Ligands

Agonists


Antagonists

  • AC927
  • AHD1
  • AZ66
  • BD1008
  • BD-1047: selective for σ1 subtype
  • BD1060: selective for σ1 subtype
  • BD1063: selective for σ1 subtype
  • BD1067
  • BMY-14802
  • CM156: 3-(4-(4-cyclohexylpiperazin-1-yl)butyl)benzo[d]thiazole-2(3H)-thione[23]
  • E-5842
  • Haloperidol
  • LR132: selective for σ1 subtype
  • LR172
  • MS-377: selective for σ1 subtype
  • NE-100: selective for σ1 subtype
  • Panamesine
  • Phenothiazines[24]
  • Progesterone
  • Rimcazole
  • S1RA (E-52862): selective for σ1 subtype
  • Sertraline
  • UMB100
  • UMB101
  • UMB103
  • UMB116
  • YZ-011
  • YZ-069
  • YZ-185


References

  1. ↑ "Sigma receptor agonists provide neuroprotection in vitro by preserving bcl-2". Anesthesia and Analgesia 104 (5): 1179–84, tables of contents. May 2007. doi:10.1213/01.ane.0000260267.71185.73. PMID 17456670. 
  2. ↑ "The hallucinogen N,N-dimethyltryptamine (DMT) is an endogenous sigma-1 receptor regulator". Science 323 (5916): 934–7. February 2009. doi:10.1126/science.1166127. PMID 19213917. Bibcode: 2009Sci...323..934F. 
  3. ↑ "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. June 2006. PMID 16845227. 
  4. ↑ 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. PMID 25566323. 
  5. ↑ Bartz, Fabian; Kern, Luise; Erz, Dorothee; Zhu, Mingang; Gilbert, Daniel; Meinhof, Till; Wirkner, Ute; Erfle, Holger et al. (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. 
  6. ↑ "Introduction to Sigma Proteins: Evolution of the Concept of Sigma Receptors". Sigma Proteins: Evolution of the Concept of Sigma Receptors. Handbook of Experimental Pharmacology. 244. Cham: Springer International Publishing. 2017. pp. 1–11. doi:10.1007/164_2017_41. ISBN 978-3-319-65853-7. 
  7. ↑ "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. July 1996. doi:10.1073/pnas.93.15.8072. PMID 8755605. Bibcode: 1996PNAS...93.8072H. 
  8. ↑ "Sigma receptors and sigma ligands: background to a pharmacological enigma". Pharmacopsychiatry 37 (Suppl 3): S166–70. November 2004. doi:10.1055/s-2004-832674. PMID 15547782. 
  9. ↑ 9.0 9.1 "The pharmacology of sigma-1 receptors". Pharmacology & Therapeutics 124 (2): 195–206. November 2009. doi:10.1016/j.pharmthera.2009.07.001. PMID 19619582. 
  10. ↑ "Sigma receptors: biology and therapeutic potential". Psychopharmacology 174 (3): 301–19. July 2004. doi:10.1007/s00213-004-1920-9. PMID 15197533. 
  11. ↑ "The hallucinogen N,N-dimethyltryptamine (DMT) is an endogenous sigma-1 receptor regulator". Science 323 (5916): 934–7. February 2009. doi:10.1126/science.1166127. PMID 19213917. Bibcode: 2009Sci...323..934F. 
  12. ↑ "Novel sigma (sigma) receptor agonists produce antidepressant-like effects in mice". European Neuropsychopharmacology 17 (11): 708–16. November 2007. doi:10.1016/j.euroneuro.2007.02.007. PMID 17376658. 
  13. ↑ Nguyen, Nhi T.; Jaramillo-Martinez, Valeria; Mathew, Marilyn; Suresh, Varshini V.; Sivaprakasam, Sathish; Bhutia, Yangzom D.; Ganapathy, Vadivel (January 2023). "Sigma Receptors: Novel Regulators of Iron/Heme Homeostasis and Ferroptosis" (in en). International Journal of Molecular Sciences 24 (19): 14672. doi:10.3390/ijms241914672. ISSN 1422-0067. PMID 37834119. 
  14. ↑ "Researchers identify long-sought activator of sigma receptors in human cells". 2019-01-14. https://www.sciencedaily.com/releases/2019/01/190114113529.htm. 
  15. ↑ "(ACMD) Methoxetamine Report (2012)" (PDF). UK Home Office. 2012-10-18. pp. 14. http://www.homeoffice.gov.uk/publications/agencies-public-bodies/acmd1/methoxetamine2012. 
  16. ↑ "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. February 1997. doi:10.1016/S0924-977X(96)00042-9. PMID 9088882. 
  17. ↑ "Evidence of a role for NMDA receptors in pain perception". European Journal of Pharmacology 187 (3): 513–8. October 1990. doi:10.1016/0014-2999(90)90379-k. PMID 1963598. 
  18. ↑ "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. November 2000. doi:10.4088/jcp.v61n1106. PMID 11105737. 
  19. ↑ "The role of lamotrigine in the management of bipolar disorder". Neuropsychiatric Disease and Treatment 3 (4): 463–74. August 2007. PMID 19300575. 
  20. ↑ "Involvement of the sigma 1 receptor in the modulation of dopaminergic transmission by amantadine". The European Journal of Neuroscience 19 (8): 2212–20. April 2004. doi:10.1111/j.0953-816X.2004.03297.x. PMID 15090047. 
  21. ↑ "Methylphenidate enhances NMDA-receptor response in medial prefrontal cortex via sigma-1 receptor: a novel mechanism for methylphenidate action". PLOS ONE 7 (12): e51910. 2012. doi:10.1371/journal.pone.0051910. PMID 23284812. Bibcode: 2012PLoSO...751910Z. 
  22. ↑ "Role of opioidergic and serotonergic mechanisms in cough and antitussives". Pulmonary Pharmacology 9 (5–6): 349–56. Oct–Dec 1996. doi:10.1006/pulp.1996.0046. PMID 9232674. 
  23. ↑ "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. May 2010. doi:10.1124/jpet.109.161398. PMID 20100904. 
  24. ↑ "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. May 2019. doi:10.1134/S1607672919010186. PMID 31012016. 

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