Orthosteric and allosteric potentiation of heteromeric neuronal nicotinic acetylcholine receptors.

ABSTRACT: Heteromeric nicotinic ACh receptors (nAChRs) were thought to have two orthodox agonist-binding sites at two α/β subunit interfaces. Highly selective ligands are hard to develop by targeting orthodox agonist sites because of high sequence similarity of this binding pocket among different subunits. Recently, unorthodox ACh-binding sites have been discovered at some α/α and β/α subunit interfaces, such as α4/α4, α5/α4 and β3/α4. Targeting unorthodox sites may yield subtype-selective ligands, such as those for (α4β2)₂ α5, (α4β2)₂ β3 and (α6β2)₂ β3 nAChRs. The unorthodox sites have unique pharmacology. Agonist binding at one unorthodox site is not sufficient to activate nAChRs, but it increases activation from the orthodox sites. NS9283, a selective agonist for

SUBMITTER: Wang J 

PROVIDER: S-EPMC5980197 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature