Neuronal nicotinic acetylcholine receptor alpha-3-beta-4 and alpha-3-alpha-5-beta-4 (nAChR α3β4 and α3α5β4)

The Neuronal nicotinic acetylcholine receptor alpha-3-beta-4 (α3β4) and its alpha-5-containing variant (α3α5β4) are pentameric ligand-gated ion channels that play a critical role in both the peripheral and central nervous systems [11, 13]. Primarily known as the "ganglionic" nicotinic receptor, the α3β4 subtype is highly expressed in the autonomic ganglia and adrenal medulla, where it mediates fast excitatory synaptic transmission [11, 15]. In the central nervous system, these receptors are localized within the medial habenula-interpeduncular nucleus (MHb-IPN) axis, a pathway significantly involved in the regulation of reward, nicotine withdrawal, and the aversive effects of high-dose nicotine [13, 18, 20]. Genetic variations within the CHRNA5-CHRNA3-CHRNB4 gene cluster, particularly the rs16969968 polymorphism in the α5 subunit, are strongly associated with an increased risk of nicotine dependence and lung cancer [1, 2, 3, 6]. Consequently, these receptors have emerged as promising therapeutic targets for treating substance use disorders, including nicotine and cocaine addiction [4, 8, 10]. Pharmacological agents such as 18-methoxycoronaridine (18-MC) and AT-1001 act as selective antagonists or partial agonists at these sites to reduce drug-seeking behavior, though achieving high subtype selectivity is essential to minimize autonomic side effects [4, 7, 11].

Other names

Ganglionic nicotinic acetylcholine receptorCHRNA3-CHRNB4 receptorCHRNA3-CHRNA5-CHRNB4 receptoralpha3beta4* nAChRNicotinic acetylcholine receptor alpha3/beta4/alpha5

Agonist, Partial agonist, Antagonist, Non-competitive antagonist, Negative allosteric modulator