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Sigma receptor

May 05, 2023

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.

ERG2/Sigma-1 receptor
Identifiers
SymbolERG2_Sigma1R
PfamPF04622
InterProIPR006716
TCDB8.A.63
OPM superfamily446
OPM protein5hk1
Membranome1025
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
Sigma intracellular receptor 2
Identifiers
SymbolSigma2
InterProIPR016964

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 (citation needed) with a mostly intracellular (ER membrane) localization.

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.[4] 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.[5] At this point, they were designated as a separate class of proteins.

Function

The function of these receptors is poorly understood.[6] 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.[7] Another endogenous ligand, N,N-dimethyltryptamine, was also found to interact with σ1.[8][9]

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. 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.[10]

Ligands

Agonists

Antagonists

References

  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. ^ 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.
  5. ^ 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. PMC 38877. PMID 8755605.
  6. ^ 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.
  7. ^ 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.
  8. ^ 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. S2CID 23606712.
  9. ^ 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.
  10. ^ 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.
  11. ^ "Researchers identify long-sought activator of sigma receptors in human cells". 2019-01-14. Retrieved 2022-03-14.
  12. ^ "(ACMD) Methoxetamine Report (2012)" (PDF). UK Home Office. 2012-10-18. p. 14. Retrieved 2012-10-22.
  13. ^ 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.
  14. ^ 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.
  15. ^ 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.
  16. ^ 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.
  17. ^ 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.
  18. ^ 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.
  19. ^ 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.
  20. ^ 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.
  21. ^ 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.

External links

May 05, 2023
sigma, receptor, this, article, technical, most, readers, understand, please, help, improve, make, understandable, experts, without, removing, technical, details, august, 2020, learn, when, remove, this, template, message, receptors, protein, cell, surface, re. This article may be too technical for most readers to understand Please help improve it to make it understandable to non experts without removing the technical details August 2020 Learn how and when to remove this template message Sigma receptors s 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 s1 and sigma 2 receptors s2 which are classified as sigma receptors for their pharmacological similarities even though they are evolutionarily unrelated ERG2 Sigma 1 receptorIdentifiersSymbolERG2 Sigma1RPfamPF04622InterProIPR006716TCDB8 A 63OPM superfamily446OPM protein5hk1Membranome1025Available protein structures Pfam structures ECOD PDBRCSB PDB PDBe PDBjPDBsumstructure summarySigma intracellular receptor 2IdentifiersSymbolSigma2InterProIPR016964The 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 citation needed with a mostly intracellular ER membrane localization Contents 1 Classification 2 Function 3 Physiologic effects 4 Ligands 4 1 Agonists 4 2 Antagonists 5 References 6 External linksClassification EditBecause the s receptor was originally discovered to be agonized by benzomorphan opioids and antagonized by naltrexone s receptors were originally believed to be a type of opioid receptor 4 When the s1 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 5 At this point they were designated as a separate class of proteins Function EditThe function of these receptors is poorly understood 6 Drugs known to be s agonists include cocaine morphine diacetylmorphine opipramol PCP fluvoxamine methamphetamine dextromethorphan and berberine citation needed However the exact role of s receptors is difficult to establish as many s agonists also bind to other targets such as the k opioid receptor and the NMDA glutamate receptor In animal experiments s antagonists such as rimcazole were able to block convulsions from cocaine overdose s 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 7 Another endogenous ligand N N dimethyltryptamine was also found to interact with s1 8 9 Physiologic effects EditPhysiologic effects when the s receptor is activated include hypertonia tachycardia tachypnea antitussive effects and mydriasis citation needed Some s receptor agonists such as cocaine a weak s agonist exert convulsant effects in animals Behavioral reactions to s agonists are rather heterogeneous some individuals find s 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 s receptor agonists were shown to produce antidepressant like effects in mice 10 Ligands EditAgonists Edit Choline 11 3 MeO PCP 12 selective for s1 subtype Ki 42nM 4 PPBP Afobazole selective for s1 subtype Allylnormetazocine SKF 10047 Anavex 2 73 7 Arketamine BD1031 selective for s1 subtype BD1052 selective for s1 subtype Berberine Citalopram Cocaine Dehydroepiandrosterone DHEA Dehydroepiandrosterone sulfate DHEA S Dextromethorphan DXM relatively selective for s1 subtype Dextrorphan N N Dimethyltryptamine DMT Dimemorfan Ditolylguanidine Escitalopram Fluoxetine Fluvoxamine Igmesine Ketamine 13 14 L 687 384 selective for s1 subtype Lamotrigine 15 16 Memantine 17 selective for s1 subtype low affinity Methamphetamine Methylphenidate 18 Noscapine 19 OPC 14523 Opipramol PB 28 selective for s2 subtype Pentazocine Pentoxyverine selective for s1 subtype Phencyclidine 3 PPP PRE 084 selective for s1 subtype Pregnenolone Pregnenolone sulfate SA 4503 selective for s1 subtype Siramesine UMB23 UMB82 Antagonists Edit AC927 AHD1 AZ66 BD1008 BD 1047 selective for s1 subtype BD1060 selective for s1 subtype BD1063 selective for s1 subtype BD1067 BMY 14802 CM156 3 4 4 cyclohexylpiperazin 1 yl butyl benzo d thiazole 2 3H thione 20 E 5842 Haloperidol LR132 selective for s1 subtype LR172 MS 377 selective for s1 subtype NE 100 selective for s1 subtype Panamesine Phenothiazines 21 Progesterone Rimcazole S1RA E 52862 selective for s1 subtype Sertraline UMB100 UMB101 UMB103 UMB116 YZ 011 YZ 069 YZ 185References Edit 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 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 Skuza G Rogoz 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 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 PMC 38877 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 a b Maurice T Su TP November 2009 The pharmacology of sigma 1 receptors Pharmacology amp Therapeutics 124 2 195 206 doi 10 1016 j pharmthera 2009 07 001 PMC 2785038 PMID 19619582 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 S2CID 23606712 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 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 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 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 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 PMC 3527396 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 Mesangeau 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 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 External links Editsigma Receptor at the U S National Library of Medicine Medical Subject Headings MeSH Retrieved from https en wikipedia org w index php title Sigma receptor amp oldid 1126663606, wikipedia, wiki, book, books, library,

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