Sigma receptor

Class of cell surface receptors

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|

ERG2/Sigma-1 receptor

Identifiers
Symbol| ERG2_Sigma1R
Pfam| PF04622
InterPro| IPR006716
TCDB| 8.A.63
OPM superfamily| 446
OPM protein| 5hk1
Membranome| 1025
| Available protein structures:

Pfam | structures / ECOD
PDB| RCSB PDB; PDBe; PDBj
PDBsum| structure summary
Sigma intracellular receptor 2

Identifiers
Symbol| Sigma2
InterPro| IPR016964

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

## Classification[edit]

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[edit]

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[edit]

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.[10]

σ-receptors were also shown to have a role in the regulation of iron/heme homeostasis.[11]

## Ligands[edit]

### Agonists[edit]

* Choline:[12]
* 3-MeO-PCP:[13] selective for σ1 subtype, Ki = 42nM
* 4-PPBP
* Afobazole: selective for σ1 subtype
* Allylnormetazocine (SKF-10047)
* Anavex 2-73[7]
* Arketamine
* BD1031: selective for σ1 subtype
* BD1052: selective for σ1 subtype
* Berberine
* Citalopram
* Cocaine
* Dehydroepiandrosterone (DHEA)
* Dehydroepiandrosterone sulfate (DHEA-S)
* Dextromethorphan (DXM): relatively selective for σ1 subtype
* Dextrorphan
* N,N-Dimethyltryptamine (DMT)
* Dimemorfan
* Ditolylguanidine
* Escitalopram
* Fluoxetine
* Fluvoxamine
* Igmesine
* Ketamine[14][15]
* L-687,384: selective for σ1 subtype
* Lamotrigine[16][17]
* Memantine:[18] selective for σ1 subtype, low affinity
* Methamphetamine
* Methylphenidate[19]
* Noscapine[20]
* OPC-14523
* Opipramol
* PB-28: selective for σ2 subtype
* Pentazocine
* Pentoxyverine: selective for σ1 subtype
* Phencyclidine
* (+)-3-PPP
* PRE-084: selective for σ1 subtype
* Pregnenolone
* Pregnenolone sulfate
* SA 4503: selective for σ1 subtype
* Siramesine
* UMB23
* UMB82

### Antagonists[edit]

* 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[21]
* E-5842
* Haloperidol
* LR132: selective for σ1 subtype
* LR172
* MS-377: selective for σ1 subtype
* NE-100: selective for σ1 subtype
* Panamesine
* Phenothiazines[22]
* Progesterone
* Rimcazole
* S1RA (E-52862): selective for σ1 subtype
* Sertraline
* UMB100
* UMB101
* UMB103
* UMB116
* YZ-011
* YZ-069
* YZ-185

## References[edit]

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. S2CID 38914893.
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. ^ 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". International Journal of Molecular Sciences. 24 (19): 14672. doi:10.3390/ijms241914672. ISSN 1422-0067. PMC 10572259. PMID 37834119.
12. ^ "Researchers identify long-sought activator of sigma receptors in human cells". 2019-01-14. Retrieved 2022-03-14.
13. ^ "(ACMD) Methoxetamine Report (2012)" (PDF). UK Home Office. 2012-10-18. p. 14. Retrieved 2012-10-22.
14. ^ 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.
15. ^ 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.
16. ^ 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.
17. ^ 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.
18. ^ 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.
19. ^ 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.
20. ^ 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.
21. ^ 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.
22. ^ 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[edit]

* sigma+Receptor at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

* v
* t
* e

Neuropeptide receptors

G protein-coupled receptor|

| Hormone receptors|

| Hypothalamic|

* CRH
* FSH
* LHRH
* TRH
* Somatostatin

|

Pituitary|

* Vasopressin
* 1A
* 1B
* 2
* Oxytocin
* LHCG
* TSH

Other|

* Atrial natriuretic factor
* NPR3
* Calcitonin
* Cholecystokinin
* A
* B
* VIP

Opioid receptors|

* Delta
* Kappa
* Mu
* Nociceptin

Other neuropeptide receptors|

* Angiotensin
* Bradykinin
* B1
* B2
* Tachykinin
* TACR1
* Calcitonin gene-related peptide
* Galanin
* GPCR neuropeptide
* B/W
* FF
* S
* Y
* Neurotensin

Type I cytokine receptor|

* GH
* Prolactin

Enzyme-linked receptor|

* Atrial natriuretic factor
* NPR1
* NPR2

Other|

* Sigma
* 1
* 2

* v
* t
* e

Sigma receptor modulators

σ1|

* Agonists: 3-PPP
* 4-PPBP
* 5-MeO-DMT
* Alazocine (SKF-10047)
* Amantadine
* Arketamine
* BD-737
* BD-1052
* Blarcamesine
* Captodiame
* Citalopram
* CGRPTooltip Calcitonin gene-related peptide
* Cloperastine
* Cocaine
* Cutamesine (SA-4503)
* Cyclazocine
* Dehydroepiandrosterone (DHEA) (prasterone)
* Dehydroepiandrosterone sulfate (DHEA-S) (prasterone sulfate)
* Dextrallorphan
* Dextromethorphan (DXM)
* Dextrorphan (DXO)
* Dimemorfan
* Dimethyltryptamine (DMT)
* Ditolylguanidine (DTG)
* Donepezil
* Eliprodil
* Escitalopram
* Fabomotizole (afobazole)
* Fluoxetine
* Fluvoxamine
* Ifenprodil
* Igmesine (JO-1784)
* IPAB
* Ketamine
* L-687384
* MDMA (midomafetamine)
* Memantine
* Methamphetamine
* Methoxetamine
* Methylphenidate
* Nepinalone
* Neuropeptide Y
* Noscapine
* OPC-14523
* Opipramol
* Pentazocine
* Pentoxyverine (carbetapentane)
* PRE-084
* Pregnenolone
* Pregnenolone sulfate
* Pridopidine
* Racemethorphan (methorphan)
* Racemorphan (morphanol)
* UMB-23
* UMB-82

* Antagonists: 3-PPP
* AC-927
* BD-1008
* BD-1031
* BD-1047
* BD-1060
* BD-1063
* BD-1067
* BMY-14802 (BMS-181100)
* CM-156
* Dup-734
* E-5842
* E-52862 (S1RA)
* Haloperidol
* LR-132
* LR-172
* MS-377
* NE-100
* NPC-16377
* Panamesine (EMD-57455)
* PD-144418
* Pentazocine
* Progesterone
* Rimcazole (BW-234U)
* Sertraline
* SR-31742A

* Allosteric modulators: Phenytoin; Positive: Methylphenylpiracetam
* SOMCL-668

* Unknown/unsorted: 3-Methoxydextrallorphan
* 3-MeO-PCP
* 4C-T-2
* 4-IBP
* 4-IPBS
* 4-MeO-PCP
* 5-MeO-DALT
* 5-MeO-DiPT
* Amitriptyline
* Azidopamil
* Chlorpromazine
* Clemastine
* Clomipramine
* Clorgiline
* D-Deprenyl
* DiPTTooltip N,N-Diisopropyltryptamine
* DPTTooltip N,N-Dipropyltryptamine
* Ibogaine
* Imipramine
* KCR-12-83.1
* Nemonapride
* Noribogaine
* RHL-033
* RS-67,333
* RTI-55
* Saffron
* Safinamide
* Selegiline
* Spipethiane
* Trifluoperazine
* W-18
* YKP10A

σ2|

* Agonists: 3-PPP
* Arketamine
* BD-1047
* BD1063
* Ditolylguanidine (DTG)
* DKR-1005
* DKR-1051
* Haloperidol
* Ifenprodil
* Ketamine
* MDMA (midomafetamine)
* Methamphetamine
* OPC-14523
* Opipramol
* PB-28
* Phencyclidine
* Siramesine (Lu 28-179)
* UKH-1114

* Antagonists: AC-927
* BD-1008
* BD-1067
* CM-156
* CT-1812
* LR-172
* MIN-101
* Panamesine (EMD-57455)
* SAS-0132

* Unknown/unsorted: 3-Methoxydextrallorphan
* 3-MeO-PCE
* 4-MeO-PCP
* 5-MeO-DALT
* 5-MeO-DiPT
* Clemastine
* DiPTTooltip N,N-Diisopropyltryptamine
* DPTTooltip N,N-Dipropyltryptamine
* Ibogaine
* Nemonapride
* Nepinalone
* Noribogaine
* Pentazocine
* RS-67,333
* Safinamide
* TMATooltip 3,4,5-Trimethoxyamphetamine
* UMB-23
* UMB-82
* W-18

Unsorted|

* Agonists: Berberine
* Ethylketazocine
* Fourphit
* Metaphit
* Naluzotan
* Tapentadol
* Tenocyclidine

* Antagonists: AHD1
* AZ66
* Lamotrigine
* Naloxone
* SM-21
* UMB-100
* UMB-101
* UMB-103
* UMB-116
* YZ-011
* YZ-069
* YZ-185

* Allosteric modulators: SKF-83959

* Unknown/unsorted: 18-Methoxycoronaridine
* BMY-13980
* Butaclamol
* Caramiphen
* Carvotroline
* Chlorphenamine (chlorpheniramine)
* Chlorpromazine
* Cinnarizine
* Cinuperone
* Clocapramine
* Dezocine
* EMD-59983
* Hypericin (St. John's wort)
* Fluphenazine
* Gevotroline (WY-47384)
* Mepyramine (pyrilamine)
* Molindone
* Perphenazine
* Pimozide
* Proadifen
* Promethazine
* Propranolol
* Quinidine
* Remoxipride
* SL 82.0715
* SR-31747A
* Tiospirone (BMY-13859)
* Venlafaxine

See also: Receptor/signaling modulators
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[CGRP]: Calcitonin gene-related peptide
*[MDMA]: Methylenedioxymethamphetamine
*[DiPT]: N,N-Diisopropyltryptamine
*[DPT]: N,N-Dipropyltryptamine
*[TMA]: 3,4,5-Trimethoxyamphetamine