Title

The Novel α7β2-Nicotinic Acetylcholine Receptor Subtype Is Expressed In Mouse And Human Basal Forebrain: Biochemical And Pharmacological Characterization

Department

neurobiology

Document Type

Article

Abstract

We examined α7β2-nicotinic acetylcholine receptor (α7β2-nAChR) expression in mammalian brain and compared pharmacological profiles of homomeric α7- nAChRs and α7β2-nAChRs. α-Bungarotoxin affinity purification or immunoprecipitation with anti-α7 subunit antibodies (Abs) was used to isolate nAChRs containing α7 subunits from mouse or human brain samples. α7β2-nAChRs were detected in forebrain, but not other tested regions, from both species, based on Western blot analysis of isolates using β2 subunit-specific Abs. Ab specificity was confirmed in control studies using subunit-null mutant mice or cell lines heterologously expressing specific human nAChR subtypes and subunits. Functional expression in Xenopus oocytes of concatenated pentameric (α7) 5-, (α7)4(β2) 1-, and (α7)3(β2) 2-nAChRs was confirmed using two-electrode voltage clamp recording of responses to nicotinic ligands. Importantly, pharmacological profiles were indistinguishable for concatenated (α7)5-nAChRs or for homomeric α7-nAChRs constituted from unlinked α7 subunits. Pharmacological profiles were similar for (α7)5-, (α7)4(β 2)1-, and (α7) 3(β2)2-nAChRs except for diminished efficacy of nicotine (normalized to acetylcholine efficacy) at α7β2- versus α7-nAChRs. This study represents the first direct confirmation of α7β 2-nAChR expression in human and mouse forebrain, supporting previous mouse studies that suggested relevance of α7β2- nAChRs in Alzheimer disease etiopathogenesis. These data also indicate that α7β2-nAChR subunit isoforms with different α7/β2 subunit ratios have similar pharmacological profiles to each other and to α7 homopentameric nAChRs. This supports the hypothesis that α7β 2-nAChR agonist activation predominantly or entirely reflects binding to α7/α7 subunit interface sites. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

Publication Date

1-1-2014

Publication Title

Molecular Pharmacology

ISSN

0026895X

Volume

86

Issue

3

First Page

306

Last Page

317

Digital Object Identifier (DOI)

10.1124/mol.114.093377

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