1.A.9.1.6
The α₄β₂ nicotinic acetylcholine receptor. The NMR structure of the transmembrane domain and the multiple anaesthetic binding sites are known (Bondarenko et al., 2012).  Mutations cause autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE; Díaz-Otero et al. 2000). Nicotinic receptors are important therapeutic targets for neuromuscular disease, addiction, epilepsy and for neuromuscular blocking agents used during surgery. This system contributes to cognitive functioning through interactions with multiple neurotransmitter systems and is implicated in various CNS disorders, i.e., schizophrenia and Alzheimer's disease. It provides an extra layer of molecular complexity by existing in two different stoichiometries determined by the subunit composition. By potentiating the action of an agonist through binding to an allosteric site, positive allosteric modulators can enhance cholinergic neurotransmission (Grupe et al. 2015). Most pentameric receptors are heteromeric. Morales-Perez et al. 2016 presented the X-ray crystallographic structure of the human α₄β₂ nicotinic receptor, the most abundant nicotinic subtype in the brain. The side chains of alpha4 L257 (9') and alpha4L264 (16') may beresponsible for the main constrictions in the transmembrane pore (Yu et al. 2019). Mechanistic steps for communication proceed (1) through a signal generated via loop C in the principal subunit, (2) transmitted gradually and cumulatively to loop F of the complementary subunit, and (3) to the TMSs through the M2-M3 linker (Oliveira et al. 2019). A genetic variant of the nicotinic receptor α4-subunit causes sleep-related hyperkinetic epilepsy via increased channel opening (Mazzaferro et al. 2022).