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Vol. 289, Issue 2, 1090-1103, May 1999

Two Pharmacologically Distinct Components of Nicotinic Receptor-Mediated Rubidium Efflux in Mouse Brain Require the beta 2 Subunit1

Michael J. Marks2, Paul Whiteaker2, Jennifer Calcaterra2, Jerry A. Stitzel2, Amy E. Bullock2, Sharon R. Grady2, Marina R. Picciotto3, Jean-Pierre Changeux4 and Allan C. Collins2

Institute for Behavioral Genetics, University of Colorado, Boulder, Colorado

Nicotinic agonist-stimulated efflux of 86Rb+ from mouse brain synaptosomes was monitored continuously by on-line radioactivity detection. The concentration-effect curve following a 5-s stimulation with acetylcholine was biphasic (EC50 = 7.2 and 550 µM). alpha -Bungarotoxin (100 nM) did not inhibit the response, but dihydro-beta -erythroidine (DHbeta E) blocked both phases with differing potency (average IC50 = .22 and 8.9 µM for responses activated by low and high acetylcholine concentrations, respectively). Differential sensitivity DHbeta E inhibition was used to measure stimulation of 86Rb+ efflux by 17 nicotinic agonists, which differed markedly in potency and efficacy. All agonists were more potent at the DHbeta E-sensitive site. Both components were inhibited by the six antagonists tested. Methyllycaconitine and DHbeta E were more potent for the DHbeta E-sensitive component, whereas hexamethonium was more potent at the DHbeta E-resistant component. Both DHbeta E-sensitive and DHbeta E-resistant responses were reduced more than 95% in beta 2-null mutant mice, establishing the requirement for the beta 2 subunit for both components. Both components were widely, but not identically, distributed throughout the brain. The DHbeta E-sensitive component appears to be identical with agonist-stimulated 86Rb+ efflux described previously and is likely to be mediated by alpha 4beta 2 receptors. The DHbeta E-resistant component is a novel, active, and widely distributed response mediated by nicotinic receptor(s) that also require the beta 2 subunit.

0022-3565/99/2892-1090$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics


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