Neuronal nicotinic acetylcholine receptor (α4β2 and α5-containing subtypes) (nAChR)

Neuronal nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels that mediate fast excitatory neurotransmission and modulate the release of various neurotransmitters in the brain [14, 15, 16]. The α4β2 subtype is the most prevalent heteromeric nAChR in the mammalian central nervous system, playing a central role in cognitive functions such as attention and memory, as well as the rewarding effects of nicotine [3, 4, 8, 11]. The α5 subunit, often found as an accessory subunit in α4β2 or α3β4 complexes, significantly influences the receptor's calcium permeability, sensitivity to agonists, and rate of desensitization [1, 2, 12]. Genetic variations in the CHRNA5-A3-B4 gene cluster, particularly the α5 subunit, are strongly associated with an increased risk of nicotine addiction, lung cancer, and chronic obstructive pulmonary disease [2, 5, 6]. Therapeutically, these receptors are targeted by partial agonists like varenicline for smoking cessation and are being investigated for their potential in treating neurodegenerative diseases like Alzheimer's and Parkinson's, as well as schizophrenia and chronic pain [4, 9, 10, 16, 18, 19]. Drugs interacting with these receptors include orthosteric agonists, partial agonists, and positive allosteric modulators, which aim to restore cholinergic balance or reduce the reinforcing effects of addictive substances [3, 9, 11]. Activation of these receptors leads to the influx of cations such as sodium and calcium, resulting in neuronal depolarization and subsequent signaling cascades [4, 9, 14]. Safety concerns associated with targeting these receptors include gastrointestinal distress, sleep disturbances, and potential neuropsychiatric symptoms, necessitating careful patient monitoring [9, 12, 14].

Other names

α4β2 nicotinic acetylcholine receptorα5-containing nicotinic acetylcholine receptorCHRNA4/CHRNB2 receptorCHRNA5-containing nAChRNeuronal nAChRα4β2* nicotinic receptor

Orthosteric agonism, partial agonism, positive allosteric modulation (PAM), and non-competitive antagonism.