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Research ArticleArticle

Two Pharmacologically Distinct Components of Nicotinic Receptor-Mediated Rubidium Efflux in Mouse Brain Require the β2 Subunit

Michael J. Marks, Paul Whiteaker, Jennifer Calcaterra, Jerry A. Stitzel, Amy E. Bullock, Sharon R. Grady, Marina R. Picciotto, Jean-Pierre Changeux and Allan C. Collins
Journal of Pharmacology and Experimental Therapeutics May 1999, 289 (2) 1090-1103;
Michael J. Marks
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Paul Whiteaker
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Jennifer Calcaterra
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Jerry A. Stitzel
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Amy E. Bullock
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Sharon R. Grady
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Marina R. Picciotto
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Jean-Pierre Changeux
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Allan C. Collins
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Abstract

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). α-Bungarotoxin (100 nM) did not inhibit the response, but dihydro-β-erythroidine (DHβE) 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 DHβE 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 DHβE-sensitive site. Both components were inhibited by the six antagonists tested. Methyllycaconitine and DHβE were more potent for the DHβE-sensitive component, whereas hexamethonium was more potent at the DHβE-resistant component. Both DHβE-sensitive and DHβE-resistant responses were reduced more than 95% in β2-null mutant mice, establishing the requirement for the β2 subunit for both components. Both components were widely, but not identically, distributed throughout the brain. The DHβE-sensitive component appears to be identical with agonist-stimulated86Rb+ efflux described previously and is likely to be mediated by α4β2 receptors. The DHβE-resistant component is a novel, active, and widely distributed response mediated by nicotinic receptor(s) that also require the β2 subunit.

Footnotes

  • Send reprint requests to: Dr. Allan C. Collins, Ph.D., Institute for Behavioral Genetics, Campus Box 447, University of Colorado, Boulder, CO 80309. E-mail:al.collins{at}colorado.edu

  • ↵1 This work was supported by research Grants DA-03194 and DA-10156 and Research Scientist Award (to A.C.C.) from the National Institute on Drug Abuse (Boulder, CO), by Collège de France, Association Française contre la Myopathie, and R.J. Reynolds Tobacco Company (Paris).

  • ↵2 Current address: Institute for Behavioral Genetics, University of Colorado, Boulder, CO 80309.

  • ↵3 Current address: Department of Psychiatry, Yale University, New Haven, CT.

  • ↵4 Current address: UA D1284 “Neurobiologie Moléculaire”, Pasteur Institute, Paris, France.

  • Abbreviations:
    ACh
    acetylcholine iodide
    A-85380
    3-(2-(S)-azetidinylmethoxy)pyridine
    ABT-418
    (S)-3-methyl-5-(1-methyl-2-pyrrodinyl)isoxazole
    DHβE
    dihydro-β-erythroidine
    DMPP
    dimethylphenylpiperazinium iodide
    MLA
    methyllycaconitine
    nAChR
    nicotinic acetylcholine receptor
    dTC
    d-tubocurarine chloride
    TMA
    tetramethylammonium chloride
    α-Bgt
    [125I]α-bungarotoxin
    P2
    crude synaptosomal pellet
    OB
    olfactory bulbs
    OT
    olfactory tubercles
    Cx
    cerebral cortex
    Se
    septum
    Hp
    hippocampus
    St
    striatum
    Hab
    habenula
    Th
    thalamus
    HT
    hypothalamus
    IPN
    interpeduncular nucleus
    MB
    midbrain
    SC
    superior colliculus
    IC
    inferior colliculus
    HB
    hindbrain
    Cb
    cerebellum
    • Received September 24, 1998.
    • Accepted December 23, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 289 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 289, Issue 2
1 May 1999
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Research ArticleArticle

Two Pharmacologically Distinct Components of Nicotinic Receptor-Mediated Rubidium Efflux in Mouse Brain Require the β2 Subunit

Michael J. Marks, Paul Whiteaker, Jennifer Calcaterra, Jerry A. Stitzel, Amy E. Bullock, Sharon R. Grady, Marina R. Picciotto, Jean-Pierre Changeux and Allan C. Collins
Journal of Pharmacology and Experimental Therapeutics May 1, 1999, 289 (2) 1090-1103;

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Research ArticleArticle

Two Pharmacologically Distinct Components of Nicotinic Receptor-Mediated Rubidium Efflux in Mouse Brain Require the β2 Subunit

Michael J. Marks, Paul Whiteaker, Jennifer Calcaterra, Jerry A. Stitzel, Amy E. Bullock, Sharon R. Grady, Marina R. Picciotto, Jean-Pierre Changeux and Allan C. Collins
Journal of Pharmacology and Experimental Therapeutics May 1, 1999, 289 (2) 1090-1103;
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