Localization of agonist and competitive antagonist binding sites on nicotinic acetylcholine receptors

• Published in: Neurochemistry international 2000-06, Vol.36 (7), p.595-645
• Main Author: Arias, Hugo Rubén
• Format: Article
• Language: English
• Subjects: a-Bungarotoxin; Animals; Binding Sites; Binding, Competitive; Biological and medical sciences; Cell receptors; Cell structures and functions; conotoxins; epibatidine; Fundamental and applied biological sciences. Psychology; Molecular and cellular biology; Monoamines receptors (catecholamine, serotonine, histamine, acetylcholine); Mutation - physiology; Nicotinic Agonists - metabolism; Nicotinic Antagonists - metabolism; Receptors, Nicotinic - chemistry; Receptors, Nicotinic - genetics; Receptors, Nicotinic - metabolism; Tissue Distribution
• ISSN: 0197-0186; 1872-9754
• DOI: 10.1016/S0197-0186(99)00154-0

Identification of all residues involved in the recognition and binding of cholinergic ligands (e.g. agonists, competitive antagonists, and noncompetitive agonists) is a primary objective to understand which structural components are related to the physiological function of the nicotinic acetylcholine receptor (AChR). The picture for the localization of the agonist/competitive antagonist binding sites is now clearer in the light of newer and better experimental evidence. These sites are located mainly on both α subunits in a pocket approximately 30–35 Å above the surface membrane. Since both α subunits are identical, the observed high and low affinity for different ligands on the receptor is conditioned by the interaction of the α subunit with other non-α subunits. This molecular interaction takes place at the interface formed by the different subunits. For example, the high-affinity acetylcholine (ACh) binding site of the muscle-type AChR is located on the αδ subunit interface, whereas the low-affinity ACh binding site is located on the αγ subunit interface. Regarding homomeric AChRs (e.g. α7, α8, and α9), up to five binding sites may be located on the αα subunit interfaces. From the point of view of subunit arrangement, the γ subunit is in between both α subunits and the δ subunit follows the α aligned in a clockwise manner from the γ. Although some competitive antagonists such as lophotoxin and α-bungarotoxin bind to the same high- and low-affinity sites as ACh, other cholinergic drugs may bind with opposite specificity. For instance, the location of the high- and the low-affinity binding site for curare-related drugs as well as for agonists such as the alkaloid nicotine and the potent analgesic epibatidine (only when the AChR is in the desensitized state) is determined by the αγ and the αδ subunit interface, respectively. The case of α-conotoxins (α-CoTxs) is unique since each α-CoTx from different species is recognized by a specific AChR type. In addition, the specificity of α-CoTxs for each subunit interface is species-dependent. In general terms we may state that both α subunits carry the principal component for the agonist/competitive antagonist binding sites, whereas the non-α subunits bear the complementary component. Concerning homomeric AChRs, both the principal and the complementary component exist on the α subunit. The principal component on the muscle-type AChR involves three loops-forming binding domains (loops A–C). Loop A (from mouse seque