Alpha-3 beta-4 nicotinic receptor

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

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

Agonists

• Acetylcholine^[5] (endogenous neuromodulator that binds non-selectively to nAChRs and mAChRs.)
• Carbachol^[5]
• Cytisine^[5]
• Epibatidine^[5]
• Nicotine^[5]
• RJR-2429^[6]

Antagonists

Competitive

• DHβE^[5]

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

• compound 5, highly selective over α4β2 and α7^[7]

Noncompetitive

• Dextromethorphan^[8][9]
• Dextrorphan^[8][9]
• Dextropropoxyphene^[10]
• Hexamethonium^[5]
• Imipramine, K(d) = 0.41 μM^[11]
• Levacetylmethadol^[10]
• Mecamylamine^[5]
• Methadone^[10]
• Tubocurarine^[5]
• Bupropion
• Reboxetine^[12]
• Ibogaine
• Voacangine
• 18-Methoxycoronaridine
• AT-1001^[13]

See also

• α3β2-Nicotinic receptor
• α4β2-Nicotinic receptor
• α7-Nicotinic receptor

References

1. Stauderman KA, Mahaffy LS, Akong M; et al. (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.
2. 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.
3. "Heterogeneity of nicotinic receptor class and subunit mRNA expression among individual parasympathetic neurons from rat intracardiac ganglia". J. Neurosci. (US National Library of Medicine) 17: 586–96. 1997. PMID 8987781.
4. "Structural and functional diversity of native brain neuronal nicotinic receptors.". Biochem. Pharmacol. (US National Library of Medicine) 78: 703–11. 2009. doi:10.1016/j.bcp.2009.05.024. PMID 19481063.
5. 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. PMID 9687574.
6. Bencherif, M.; Schmitt, J. D.; Bhatti, B. S.; Crooks, P.; Caldwell, W. S.; Lovette, M. E.; Fowler, K.; Reeves, L.; Lippiello, P. M. (1998). "The heterocyclic substituted pyridine derivative (+/-)-2-(-3-pyridinyl)-1-azabicyclo2.2.2octane (RJR-2429): A selective ligand at nicotinic acetylcholine receptors". The Journal of Pharmacology and Experimental Therapeutics 284 (3): 886–894. PMID 9495846.
7. Zaveri NT (2011). "The nociceptin/orphanin FQ receptor (NOP) as a target for drug abuse medications". Curr Top Med Chem 11 (9): 1151–6. doi:10.2174/156802611795371341. PMID 21050175.
8. Hernandez SC, Bertolino M, Xiao Y, Pringle KE, Caruso FS, Kellar KJ (2000). "Dextromethorphan and its metabolite dextrorphan block alpha3beta4 neuronal nicotinic receptors". J. Pharmacol. Exp. Ther. 293 (3): 962–7. PMID 10869398.
9. 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.
10. "Blockade of Rat α3β4 Nicotinic Receptor Function by Methadone, Its Metabolites, and Structural Analogs — JPET".
11. 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". Neurochem. Int. 56 (4): 642–9. doi:10.1016/j.neuint.2010.01.011. PMID 20117161.
12. Miller, DK; Wong, EH; Chesnut, MD; Dwoskin, LP (Aug 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.
13. Toll, L.; Zaveri, N. T.; Polgar, W. E.; Jiang, F.; Khroyan, T. V.; Zhou, W.; Xie, X. (S.); Stauber, G. B.; Costello, M. R.; Leslie, F. M. (2012). "AT-1001: A High Affinity and Selective α3β4 Nicotinic Acetylcholine Receptor Antagonist Blocks Nicotine Self-Administration in Rats". Neuropsychopharmacology 37 (6): 1367–1376. doi:10.1038/npp.2011.322. PMC 3327842. PMID 22278092.