The Human Alpha3 Beta2 Neuronal Nicotinic Acetylcholine Receptor Can Form Two Distinguishable Subtypes

TL;DR

Human alpha3 beta2 nicotinic receptors can form two distinct subtypes with different functions, which may lead to new treatments for brain disorders.

Contribution

Identification of two distinct functional subtypes of human α3β2 nicotinic acetylcholine receptors based on subunit stoichiometry.

Findings

Two α3β2 nicotinic acetylcholine receptor subtypes differ in desensitization kinetics and acetylcholine affinity.

A 1:5 α3:β2 mRNA ratio yields higher acetylcholine affinity and greater desensitization than a 5:1 ratio.

Distinct α3β2 subtypes could be novel targets for cognitive therapeutics in neurological disorders.

Abstract

Diverse neuronal nicotinic acetylcholine receptor (nAChR) subtypes are expressed in hippocampal interneurons. Single-cell analysis of mRNA expression previously revealed prominent co-expression of the α3 and β2 subunits within rat interneurons in the CA1 region. Although the α3 subunit (traditionally expressed together with β4) is usually associated with the peripheral nervous system, its significant co-expression with the β2 subunit in hippocampal interneurons suggests a distinct, potentially novel central nervous system nAChR subtype. We demonstrate that the human α3 and β2 subunits injected into Xenopus laevis oocytes can assemble into at least two functionally distinct subtypes of nAChRs based on different subunit stoichiometries. These subtypes exhibit similar reversal potentials but differ significantly in their desensitization kinetics and acetylcholine (ACh) affinities. The response obtained from a 1:5 α3:β2 mRNA injection ratio shows a higher affinity for ACh and significantly greater desensitization during prolonged ACh application compared to the response obtained from a 5:1 α3:β2 mRNA injection ratio. The identification of distinct functional α3β2 subtypes, characterized by differential desensitization kinetics and ACh affinity, could represent novel targets for the potential development of highly selective cognitive therapeutics for conditions such as Alzheimer’s disease, autism spectrum disorder, and attention deficit hyperactivity disorder, where hippocampal nAChRs are implicated.

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