Pharmacological and null mutation approaches reveal nicotinic receptor diversity

Paul Whiteaker, Michael J. Marks, Sharon R. Grady, Ying Lu, Marina R. Picciotto, Jean Pierre Changeux, Allan C. Collins

Research output: Contribution to journalArticlepeer-review

Abstract

We have developed an array of assays for nicotinic acetylcholine receptor binding and function. [125I]α-Bungarotoxin-, (-)-[3H]nicotine-, and [3H]epibatidine-binding nicotinic acetylcholine receptors were assayed in mouse brain membranes and sections. Nicotinic acetylcholine receptor function was quantified using synaptosomal [3H]dopamine, [3H]γ-aminobutyric acid ([3H]GABA), and 86Rb+ efflux techniques. Additionally, the effects of β2 subunit deletion on each of the measures were assessed. Detailed pharmacological comparison revealed minimally six nicotinic binding subtypes: [125I]α-bungarotoxin-binding nicotinic acetylcholine receptors; β2-subunit-dependent and -independent high-affinity (-)-[3H]nicotine-binding sites; β2-dependent and -independent cytisine-resistant [3H]epibatidine-binding sites; and a β2-dependent low-affinity [3H]epibatidine binding site. Comparative pharmacology suggested that [3H]GABA and dihydro-β-erythroidine (DHβE)-sensitive 86Rb+ efflux are mediated by the same (probably α4β2) nicotinic acetylcholine receptor subtype, while other nicotinic acetylcholine receptor subtypes evoke [3H]dopamine and DHβE-resistant 86Rb+ efflux. In whole-brain preparations, each measure of nicotinic acetylcholine receptor function was β2 dependent. The majority of β2-independent [3H]epibatidine binding was located in small, scattered brain nuclei, suggesting that individual nuclei may prove suitable for identification of novel, native nicotinic acetylcholine receptors. Copyright (C) 2000 Elsevier Science B.V.

Original languageEnglish (US)
Pages (from-to)123-135
Number of pages13
JournalEuropean Journal of Pharmacology
Volume393
Issue number1-3
DOIs
StatePublished - Mar 30 2000

Keywords

  • Activation
  • Binding
  • Nicotinic acetylcholine receptor
  • Pharmacological comparison
  • Subunit null mutation

ASJC Scopus subject areas

  • Pharmacology

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