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Mol Pharmacol. 2003 Feb;63(2):311-24.

Relating neuronal nicotinic acetylcholine receptor subtypes defined by subunit composition and channel function.

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  • 1Department of Anatomy and Neurobiology, Medical College of Ohio, Toledo, Ohio 43614, USA.

Abstract

Neuronal nicotinic acetylcholine receptors (nAChRs) are widespread, diverse ion channels involved in synaptic signaling, addiction, and disease. Despite their importance, the relationship between native nAChR subunit composition and function remains poorly defined. Chick ciliary ganglion neurons express two major nAChR types: those recognized by alpha-bungarotoxin (alphaBgt), nearly all of which contain only alpha7 subunits (alpha7-nAChRs) and those insensitive to alphaBgt, which contain alpha3, alpha5, beta4, and, in some cases, beta2 subunits (alpha3*-nAChRs). We explored the relationship between nAChR composition and channel function using toxins recognizing alpha7 subunits (alphaBgt), and alpha3/beta4 (alpha-conotoxin-AuIB), or alpha3/beta2 (alpha-conotoxin-MII) subunit interfaces to perturb responses induced by nicotine, alpha7-, or alpha3-selective agonists (GTS-21 or epibatidine, respectively). Using these reagents, fast-decaying whole-cell current components were attributed solely to alpha7-nAChRs, and slow-decaying components mostly to alpha3*-nAChRs. In outside-out patches, nicotine activated brief 60- and 80-pS single nAChR channel events, and mixed-duration 25- and 40-pS nAChR events. Subsequently, 60- and 80-pS nAChR events and most brief 25- and 40-pS events were attributed to alpha7-nAChRs, and long 25- and 40-pS events to alpha3*-nAChRs. alpha3*-nAChRs lacking beta2 subunits seemed responsible for long 25 pS nAChR events, whereas those containing beta2 subunits mediated the long 40 pS nAChR events that dominate single-channel records. These results reveal greater functional heterogeneity for alpha7-nAChRs than previously expected and indicate that beta2 subunits contribute importantly to alpha3*-nAChR function. By linking structural to functional nAChR subtypes, the findings also illustrate a useful pharmacological strategy for selectively targeting nAChRs.

PMID:
12527802
[PubMed - indexed for MEDLINE]
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