Structural Insights into the Role of β3 nAChR Subunit in the Activation of Nicotinic Receptors

The beta 3 subunit of nicotinic acetylcholine receptors (nAChRs) participates in heteropentameric assemblies with some alpha and other beta neuronal subunits forming a plethora of various subtypes, differing in their electrophysiological and pharmacological properties. While beta 3 has for several years been considered an accessory subunit without direct participation in the formation of functional binding sites, recent electrophysiology data have disputed this notion and indicated the presence of a functional (+) side on the extracellular domain (ECD) of beta 3. In this study, we present the 2.4 angstrom resolution crystal structure of the monomeric beta 3 ECD, which revealed rather distinctive loop C features as compared to those of alpha nAChR subunits, leading to intramolecular stereochemical hindrance of the binding site cavity. Vigorous molecular dynamics simulations in the context of full length pentameric beta 3-containing nAChRs, while not excluding the possibility of a beta 3 (+) binding site, demonstrate that this site cannot efficiently accommodate the agonist nicotine. From the structural perspective, our results endorse the accessory rather than functional role of the beta 3 nAChR subunit, in accordance with earlier functional studies on beta 3-containing nAChRs.

Automated summary

The beta 3 subunit of nicotinic acetylcholine receptors (nAChRs) has been considered an accessory subunit, but recent research suggests that it may have a functional role. The crystal structure of the beta 3 extracellular domain (ECD) shows distinctive features that hinder the binding site cavity, and molecular dynamics simulations demonstrate that the site cannot efficiently accommodate nicotine. These findings support the accessory role of the beta 3 subunit.