NACHR Analysis

The nAChR is unusual among receptors in that agonist-induced desensitization leads to an up-regulation of the receptor. Ligand interactions occur with various discrete forms of the receptor as originally proposed in 1958 by Katz and Thesleff, e.g., open, resting, and desensitized states that are in equilibrium (Lena and Changeux, 1993). In addition to the acetylcholine (ACh) binding site, the nAChR, like other LGICs, e.g., GABAA(benzodiazepine, neurosteroid, and barbiturate) andN-methyl-D-aspartate (glycine and polyamine), has binding sites for other types of ligand that can modify the equilibrium between the receptor states thus representing the classical allosteric receptor. Site-directed mutagenesis has shown that the binding site(s) for cholinergic agonists e.g., ACh, (−)-nicotine, cytisine, and antagonists, e.g., neuronal bungarotoxin (n-BgT), dihydro-β-erythroidine
These compounds modulate nAChR function via interactions at two distinct sites that differ from those where competitive blockers act. The first site is present on the M2 transmembrane segments of the nAChR within the pore and binds NCBs in the low micromolar range. This binding is facilitated by the presence of agonist and is thus use-dependent. Ligands acting at this site produce either a rapid reversible channel blockade or shorten channel opening time in a voltage-sensitive manner (Lena and Changeux, 1993). At the second low-affinity site, NCBs accelerate nAChR desensitization, shifting the equilibrium toward the desensitized state. Because the ligands that bind to this second site are generally lipophilic, these sites appear to lie at the interface between the nAChR protein and membrane