Biology:Sigma receptor

From HandWiki
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 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. Some early literature proposed a third subtype ("sigma-3") based on phenylaminotetralin (PAT) ligands, but later work showed this binding corresponded to the histamine H1 receptor; "sigma-3" is not recognized in current nomenclature.[4][5][6]

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 EXPERA domain protein[7] with a mostly intracellular (ER membrane) localization.[8]

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.[9] 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.[10] At this point, they were designated as a separate class of proteins.

Putative sigma-3 receptor

In the early 1990s, a "sigma-3" binding site was proposed based on phenylaminotetralin (PAT) ligands and functional assays that linked PAT binding to stimulation of tyrosine hydroxylase and dopamine synthesis in rodent brain.[4][5] Subsequent pharmacological and radioligand-binding studies demonstrated that these so-called sigma-3 sites correspond to histamine H1 receptors rather than a distinct sigma receptor subtype.[6] As a result, contemporary classifications recognize only sigma-1 and sigma-2 receptors.

Function

The function of these receptors is poorly understood.[11] Drugs known to be σ-agonists include cocaine, morphine/diacetylmorphine, opipramol, PCP, fluvoxamine, methamphetamine, dextromethorphan, and 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. Early rodent studies reported that σ-receptor ligands can functionally antagonize opioid analgesia: (+)-pentazocine and 1,3-di(2-tolyl)guanidine reduced morphine analgesia in a haloperidol-reversible, D2-independent manner, consistent with a tonically active anti-opioid σ1 system.[12][13]

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.[14] Another endogenous ligand, N,N-dimethyltryptamine, was also found to interact with σ1.[15][16]

Physiologic effects

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. In 2007, selective σ-receptor agonists were shown to produce antidepressant-like effects in mice.[17]

σ-receptors were also shown to have a role in the regulation of iron/heme homeostasis.[18]

In mice, σ1 activation attenuated μ-, κ-, and δ-opioid analgesia without altering morphine's effects on gastrointestinal transit or lethality, while σ blockade with haloperidol enhanced analgesia and eliminated strain differences in κ-agonist sensitivity.[13]

Ligands

Agonists

Antagonists

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. ↑ 4.0 4.1 "Conformational analysis, pharmacophore identification, and comparative molecular field analysis of ligands for the neuromodulatory sigma 3 receptor". Journal of Medicinal Chemistry 37 (24): 4109–4117. 1994-11-25. doi:10.1021/jm00050a008. PMID 7990111. 
  5. ↑ 5.0 5.1 "1-Phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes and related derivatives as ligands for the neuromodulatory sigma-3 receptor: further structure–activity relationships". Journal of Medicinal Chemistry 38 (19): 3857–3864. 1995-09-15. doi:10.1021/jm00019a016. PMID 7562917. 
  6. ↑ 6.0 6.1 "Putative sigma(3) sites in mammalian brain have histamine H(1) receptor properties: evidence from ligand binding and distribution studies with the novel H(1) radioligand [(3)H]-(-)-trans-1-phenyl-3-aminotetralin". Brain Research 873 (1-2): 95-105. 1999-08-07. doi:10.1016/s0006-8993(99)01602-9. PMID 10433992. 
  7. ↑ 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. 
  8. ↑ 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. 
  9. ↑ "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. 
  10. ↑ "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. 
  11. ↑ "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. 
  12. ↑ "Functional antagonism of morphine analgesia by (+)-pentazocine: evidence for an anti-opioid sigma 1 system". European Journal of Pharmacology 250 (1): R7–R8. 1993-11-30. doi:10.1016/0014-2999(93)90650-7. PMID 8119306. 
  13. ↑ 13.0 13.1 "Selective antagonism of opioid analgesia by a sigma system". Journal of Pharmacology and Experimental Therapeutics 271 (3): 1583–1590. 1994. PMID 7996472. 
  14. ↑ 14.0 14.1 "The pharmacology of sigma-1 receptors". Pharmacology & Therapeutics 124 (2): 195–206. November 2009. doi:10.1016/j.pharmthera.2009.07.001. PMID 19619582. 
  15. ↑ "Sigma receptors: biology and therapeutic potential". Psychopharmacology 174 (3): 301–19. July 2004. doi:10.1007/s00213-004-1920-9. PMID 15197533. 
  16. ↑ "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. 
  17. ↑ "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. 
  18. ↑ 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). doi:10.3390/ijms241914672. ISSN 1422-0067. PMID 37834119. 
  19. ↑ "Researchers identify long-sought activator of sigma receptors in human cells". 2019-01-14. https://www.sciencedaily.com/releases/2019/01/190114113529.htm. 
  20. ↑ "(ACMD) Methoxetamine Report (2012)" (PDF). UK Home Office. 2012-10-18. p. 14. http://www.homeoffice.gov.uk/publications/agencies-public-bodies/acmd1/methoxetamine2012. 
  21. ↑ "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. 
  22. ↑ "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. 
  23. ↑ "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. 
  24. ↑ "Methylphenidate enhances NMDA-receptor response in medial prefrontal cortex via sigma-1 receptor: a novel mechanism for methylphenidate action". PLOS ONE 7 (12). 2012. doi:10.1371/journal.pone.0051910. PMID 23284812. Bibcode: 2012PLoSO...751910Z. 
  25. ↑ "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. 
  26. ↑ "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. 
  27. ↑ "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. 
  28. ↑ "Novel analogs of the sigma receptor ligand BD1008 attenuate cocaine-induced toxicity in mice". Eur J Pharmacol 492 (1): 21–6. May 2004. doi:10.1016/j.ejphar.2004.03.037. PMID 15145701. 
  29. ↑ "N-[2-(m-methoxyphenyl)ethyl]-N-ethyl-2-(1-pyrrolidinyl)ethylamine (UMB 116) is a novel antagonist for cocaine-induced effects". Eur J Pharmacol 542 (1-3): 61–8. August 2006. doi:10.1016/j.ejphar.2006.03.062. PMID 16797004. 
  30. ↑ "The sigma receptor ligand N-phenylpropyl-N'-(4-methoxyphenethyl)3piperazine (YZ-067) enhances the cocaine conditioned-rewarding properties while inhibiting the development of sensitization of cocaine in mice". Psychopharmacology (Berl) 237 (3): 723–734. March 2020. doi:10.1007/s00213-019-05411-z. PMID 31822924. 
  31. ↑ "Structure-activity comparison of YZ-069, a novel sigma ligand, and four analogs in receptor binding and behavioral studies". Pharmacol Biochem Behav 77 (4): 775–81. April 2004. doi:10.1016/j.pbb.2004.01.014. PMID 15099923. 
  32. ↑ "N-Phenylpropyl-N'-(3-methoxyphenethyl)piperazine (YZ-185) Attenuates the Conditioned-Rewarding Properties of Cocaine in Mice". ISRN Pharmacol 2013. 2013. doi:10.1155/2013/546314. PMID 24089641. 



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