Alpha-3 beta-4 nicotinic receptor

The alpha-3 beta-4 nicotinic receptor, also known as the α3β4 receptor and the ganglion-type nicotinic receptor,^[1] is a type of nicotinic acetylcholine receptor, consisting of α3 and β4 subunits.^[2][3] It is located in the autonomic ganglia^[4] and adrenal medulla,^[5] where activation yields post- and/or presynaptic excitation,^[3] mainly by increased Na⁺ and K⁺ permeability.

As with other nicotinic acetylcholine receptors, the α3β4 receptor is pentameric [(α3)_m(β4)_n where m + n = 5]. The exact subunit stoichiometry is not known and it is possible that more than one functional α3β4 receptor assembles in vivo with varying subunit stoichiometries.

Ligands which inhibit the α3β4 receptor have been shown to modulate drug-seeking behavior,^[6] making α3β4 a promising target for the development of novel antiaddictive agents.

Ligands

Source:^[7]

Agonists

• Acetylcholine^[8] (endogenous neurotransmitter that binds non-selectively to nAChRs and mAChRs)
• Anabaseine and other structural analogs^[9]
• Carbachol^[8]
• Cytisine (partial agonist) ^[8]
• Dimethylphenylpiperazinium^[10]
• Epibatidine^[8]
• Lobeline^[11]
• Nicotine^[8]
• RJR-2429^[12]

Antagonists

Competitive

3d structure of "compound 5" (Zaveri 2010). K_i, 508 nM at α₃β₄ nAChR

• DHβE^[8]
• SR 16584,^[13] highly selective over α4β2 and α7^[14]

Noncompetitive

• Dextromethorphan^[15][16]
• Dextrorphan^[15][16]
• Dextropropoxyphene^[17]
• Hexamethonium^[8]
• Imipramine^[18]
• Levacetylmethadol^[17]
• Mecamylamine^[8]
• Methadone^[17]
• Tubocurarine^[8]
• Bupropion
• Reboxetine^[19]
• Ibogaine
• Voacangine
• 18-MC
• 18-MAC
• ME-18-MC
• AT-1001^[20]
• Choline^[21]

See also

• α3β2-Nicotinic receptor
• α4β2-Nicotinic receptor
• α7-Nicotinic receptor
• Muscle-type nicotinic receptor

References

1. Pharmacology, (Rang, Dale, Ritter & Moore, ISBN 0-443-07145-4, 5th ed., Churchill Livingstone 2003) p. 138.
2. Stauderman KA, Mahaffy LS, Akong M, Veliçelebi G, Chavez-Noriega LE, Crona JH, Johnson EC, Elliott KJ, Gillespie A, Reid RT, Adams P, Harpold MM, Corey-Naeve J (February 1998). "Characterization of human recombinant neuronal nicotinic acetylcholine receptor subunit combinations alpha2beta4, alpha3beta4 and alpha4beta4 stably expressed in HEK293 cells". The Journal of Pharmacology and Experimental Therapeutics. 284 (2): 777–89. PMID 9454827.
3. Xiao Y, Kellar KJ (July 2004). "The comparative pharmacology and up-regulation of rat neuronal nicotinic receptor subtype binding sites stably expressed in transfected mammalian cells". The Journal of Pharmacology and Experimental Therapeutics. 310 (1): 98–107. doi:10.1124/jpet.104.066787. PMID 15016836. S2CID 23900581.
4. Poth K, Nutter TJ, Cuevas J, Parker MJ, Adams DJ, Luetje CW (January 1997). "Heterogeneity of nicotinic receptor class and subunit mRNA expression among individual parasympathetic neurons from rat intracardiac ganglia". The Journal of Neuroscience. 17 (2). US National Library of Medicine: 586–96. doi:10.1523/JNEUROSCI.17-02-00586.1997. PMC 6573231. PMID 8987781.
5. Gotti C, Clementi F, Fornari A, Gaimarri A, Guiducci S, Manfredi I, Moretti M, Pedrazzi P, Pucci L, Zoli M (October 2009). "Structural and functional diversity of native brain neuronal nicotinic receptors" (PDF). Biochemical Pharmacology. 78 (7). US National Library of Medicine: 703–11. doi:10.1016/j.bcp.2009.05.024. PMID 19481063.
6. HarringtonEtAl, L. (2015). "Role of β4* Nicotinic Acetylcholine Receptors in the Habenulo–Interpeduncular Pathway in Nicotine Reinforcement in Mice". Neuropsychopharmacology. 41 (7): 1790–1802. doi:10.1038/npp.2015.346. PMC 4869047. PMID 26585290.
7. Matera, Carlo; Papotto, Claudio; Dallanoce, Clelia; De Amici, Marco (2023-08-01). "Advances in small molecule selective ligands for heteromeric nicotinic acetylcholine receptors". Pharmacological Research. 194: 106813. doi:10.1016/j.phrs.2023.106813. hdl:2434/978688. ISSN 1043-6618. PMID 37302724.
8. Xiao Y, Meyer EL, Thompson JM, Surin A, Wroblewski J, Kellar KJ (August 1998). "Rat alpha3/beta4 subtype of neuronal nicotinic acetylcholine receptor stably expressed in a transfected cell line: pharmacology of ligand binding and function". Molecular Pharmacology. 54 (2): 322–33. doi:10.1124/mol.54.2.322. PMID 9687574.
9. Matera C, Quadri M, Sciaccaluga M, Pomè DY, Fasoli F, De Amici M, Fucile S, Gotti C, Dallanoce C, Grazioso G (January 2016). "Modification of the anabaseine pyridine nucleus allows achieving binding and functional selectivity for the α3β4 nicotinic acetylcholine receptor subtype". European Journal of Medicinal Chemistry. 108: 392–405. doi:10.1016/j.ejmech.2015.11.045. hdl:2434/352478. PMID 26706350.
10. Prado WA, Segalla DK (2004). "Antinociceptive effects of bethanechol or dimethylphenylpiperazinium in models of phasic or incisional pain in rats". Brain Res. 1018 (2): 272–82. doi:10.1016/j.brainres.2004.05.085. PMID 15276888. S2CID 45145197.
11. Rang, H. P. (2003), Pharmacology, Edinburgh: Churchill Livingstone, ISBN 0-443-07145-4 Page 149
12. Bencherif M, Schmitt JD, Bhatti BS, Crooks P, Caldwell WS, Lovette ME, Fowler K, Reeves L, Lippiello PM (March 1998). "The heterocyclic substituted pyridine derivative (+/-)-2-(-3-pyridinyl)-1-azabicyclo[2.2.2]octane (RJR-2429): a selective ligand at nicotinic acetylcholine receptors". The Journal of Pharmacology and Experimental Therapeutics. 284 (3): 886–94. PMID 9495846.
13. "SR 16584 (CAS 1150153-86-8)". R&D Systems. Retrieved 3 December 2017.
14. Zaveri, NT (2011). "The nociceptin/orphanin FQ receptor (NOP) as a target for drug abuse medications". Current Topics in Medicinal Chemistry. 11 (9): 1151–6. doi:10.2174/156802611795371341. PMC 3899399. PMID 21050175.
15. Hernandez SC, Bertolino M, Xiao Y, Pringle KE, Caruso FS, Kellar KJ (June 2000). "Dextromethorphan and its metabolite dextrorphan block alpha3beta4 neuronal nicotinic receptors". The Journal of Pharmacology and Experimental Therapeutics. 293 (3): 962–7. PMID 10869398.
16. Damaj MI, Flood P, Ho KK, May EL, Martin BR (February 2005). "Effect of dextrometorphan and dextrorphan on nicotine and neuronal nicotinic receptors: in vitro and in vivo selectivity". The Journal of Pharmacology and Experimental Therapeutics. 312 (2): 780–5. doi:10.1124/jpet.104.075093. PMID 15356218. S2CID 149958.
17. Xiao, Yingxian; Smith, Richard D.; Caruso, Frank S.; Kellar, Kenneth J. (October 2001). "Blockade of Rat α3β4 Nicotinic Receptor Function by Methadone, Its Metabolites, and Structural Analogs — JPET". Journal of Pharmacology and Experimental Therapeutics. 299 (1): 366–371.
18. Arias HR, Targowska-Duda KM, Feuerbach D, Sullivan CJ, Maciejewski R, Jozwiak K (March 2010). "Different interaction between tricyclic antidepressants and mecamylamine with the human alpha3beta4 nicotinic acetylcholine receptor ion channel". Neurochemistry International. 56 (4): 642–9. doi:10.1016/j.neuint.2010.01.011. PMID 20117161. S2CID 29461221.
19. Miller DK, Wong EH, Chesnut MD, Dwoskin LP (August 2002). "Reboxetine: functional inhibition of monoamine transporters and nicotinic acetylcholine receptors". The Journal of Pharmacology and Experimental Therapeutics. 302 (2): 687–95. doi:10.1124/jpet.302.2.687. PMID 12130733.
20. Toll L, Zaveri NT, Polgar WE, Jiang F, Khroyan TV, Zhou W, Xie XS, Stauber GB, Costello MR, Leslie FM (May 2012). "AT-1001: a high affinity and selective α3β4 nicotinic acetylcholine receptor antagonist blocks nicotine self-administration in rats". Neuropsychopharmacology. 37 (6): 1367–76. doi:10.1038/npp.2011.322. PMC 3327842. PMID 22278092.
21. González-Rubioa JM, Rojoa J, Tapiaa L, Maneud V, Muletc J, Valorc LM, Criadoc M, Salac F, García AG, Gandía L (2004). "Choline as a tool to evaluate nicotinic receptor function in chromaffin cells" (PDF). In Borges R, Gandía L (eds.). Cell Biology of the Chromaffin Cell. Spain: Instituto Teófilo Hernando.