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Research ArticleArticle

Cerebellar γ-Aminobutyric Acid Type A Receptors: Pharmacological Subtypes Revealed by Mutant Mouse Lines

Riikka Mäkelä, Mikko Uusi-Oukari, Gregg E. Homanics, Joseph J. Quinlan, Leonard L. Firestone, William Wisden and Esa R. Korpi
Molecular Pharmacology September 1997, 52 (3) 380-388; DOI: https://doi.org/10.1124/mol.52.3.380
Riikka Mäkelä
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Mikko Uusi-Oukari
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Gregg E. Homanics
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Joseph J. Quinlan
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Leonard L. Firestone
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William Wisden
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Esa R. Korpi
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Abstract

The vast molecular heterogeneity of brain γ-aminobutyric acid type A (GABAA) receptors forms the basis for receptor subtyping. Using autoradiographic techniques, we established the characteristics of cerebellar granule cell GABAA receptors by comparing wild-type mice with those with a targeted disruption of the α6 subunit gene. Cerebellar granule cells of α6−/− animals have severe deficits in high affinity [3H]muscimol and [3H]SR 95531 binding to GABA sites, in agonist-insensitive [3H]Ro 15–4513 binding to benzodiazepine sites, and in furosemide-induced increases intert-[35S]butylbicyclophosphorothionate binding to picrotoxin-sensitive convulsant sites. These observations agree with the known specific properties of these sites on recombinant α6β2/3γ2 receptors. In the presence of GABA concentrations that fail to activate α1 subunit-containing receptors, methyl-6,7-dimethoxy-4-ethyl-β-carboline (30 μm), allopregnanolone (100 nm), and Zn2+ (10 μm) are less efficacious in alteringtert-[35S]butylbicyclophosphorothionate binding in the granule cell layer of the α6−/− than α6+/+ animals. These data concur with the deficiency of the cerebellar α6 and δ subunit-containing receptors in the α6−/− animals and could also account for the decreased affinity of [3H]muscimol binding to α6−/−cerebellar membranes. Predicted additional alterations in the cerebellar receptors of the mutant mice may explain a surplus of methyl-6,7-dimethoxy-4-ethyl-β-carboline-insensitive receptors in the α6−/− granule cell layer and an increased diazepam-sensitivity in the molecular layer. These changes may be adaptive consequences of altered GABAA receptor subunit expression patterns in response to the loss of two subunits (α and δ) from granule cells.

Footnotes

    • Received March 26, 1997.
    • Accepted May 29, 1997.
  • Send reprint requests to: Dr. E. R. Korpi, Department of Pharmacology and Clinical Pharmacology, University of Turku, FIN-20520 Turku, Finland. E-mail:esa.korpi{at}utu.fi

  • This work was supported in part by the Academy of Finland (E.R.K.), Finnish Foundation for Alcohol Studies (R.M.), National Institutes of Health (G.E.H., L.L.F.), and Medical Research Council (W.W.).

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 52 (3)
Molecular Pharmacology
Vol. 52, Issue 3
1 Sep 1997
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Research ArticleArticle

Cerebellar γ-Aminobutyric Acid Type A Receptors: Pharmacological Subtypes Revealed by Mutant Mouse Lines

Riikka Mäkelä, Mikko Uusi-Oukari, Gregg E. Homanics, Joseph J. Quinlan, Leonard L. Firestone, William Wisden and Esa R. Korpi
Molecular Pharmacology September 1, 1997, 52 (3) 380-388; DOI: https://doi.org/10.1124/mol.52.3.380

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Research ArticleArticle

Cerebellar γ-Aminobutyric Acid Type A Receptors: Pharmacological Subtypes Revealed by Mutant Mouse Lines

Riikka Mäkelä, Mikko Uusi-Oukari, Gregg E. Homanics, Joseph J. Quinlan, Leonard L. Firestone, William Wisden and Esa R. Korpi
Molecular Pharmacology September 1, 1997, 52 (3) 380-388; DOI: https://doi.org/10.1124/mol.52.3.380
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