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Molecular Pharmacology

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Research ArticleArticle

Effect of α Subunit on Allosteric Modulation of Ion Channel Function in Stably Expressed Human Recombinant γ-Aminobutyric AcidA Receptors Determined Using36Cl Ion Flux

Alison J. Smith, Luanda Alder, Jonathan Silk, Charles Adkins, Alan E. Fletcher, Tim Scales, Julie Kerby, George Marshall, Keith A. Wafford, Ruth M. McKernan and John R. Atack
Molecular Pharmacology May 2001, 59 (5) 1108-1118; DOI: https://doi.org/10.1124/mol.59.5.1108
Alison J. Smith
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, United Kingdom
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Luanda Alder
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, United Kingdom
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Jonathan Silk
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, United Kingdom
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Charles Adkins
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, United Kingdom
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Alan E. Fletcher
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, United Kingdom
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Tim Scales
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, United Kingdom
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Julie Kerby
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, United Kingdom
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George Marshall
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, United Kingdom
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Keith A. Wafford
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, United Kingdom
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Ruth M. McKernan
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, United Kingdom
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John R. Atack
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, United Kingdom
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Abstract

Inhibitory γ-aminobutyric acid (GABA)A receptors are subject to modulation at a variety of allosteric sites, with pharmacology dependent on receptor subunit combination. The influence of different α subunits in combination with β3γ2s was examined in stably expressed human recombinant GABAA receptors by measuring 36Cl influx through the ion channel pore. Muscimol and GABA exhibited similar maximal efficacy at each receptor subtype, although muscimol was more potent, with responses blocked by picrotoxin and bicuculline. Receptors containing the α3 subunit exhibited slightly lower potency. The comparative pharmacology of a range of benzodiazepine site ligands was examined, revealing a range of intrinsic efficacies at different receptor subtypes. Of the diazepam-sensitive GABAA receptors (α1, α2, α3, α5), α5 showed the most divergence, being discriminated by zolpidem in terms of very low affinity, and CL218,872 and CGS9895 with different efficacies. Benzodiazepine potentiation at α3β3γ2s with nonselective agonist chlordiazepoxide was greater than at α1, α2, or α5 (P < 0.001). The presence of an α4 subunit conferred a unique pharmacological profile. The partial agonist bretazenil was the most efficacious benzodiazepine, despite lower α4 affinity, and FG8205 displayed similar efficacy. Most striking were the lack of affinity/efficacy for classical benzodiazepines and the relatively high efficacy of Ro15-1788 (53 ± 12%), CGS8216 (56 ± 6%), CGS9895 (65 ± 6%), and the weak partial inverse agonist Ro15-4513 (87 ± 5%). Each receptor subtype was modulated by pentobarbital, loreclezole, and 5α-pregnan-3α-ol-20-one, but the type of α subunit influenced the level of potentiation. The maximal pentobarbital response was significantly greater at α4β3γ2s (226 ± 10% increase in the EC20 response to GABA) than any other modulator. The rank order of potentiation for pregnanolone was α5 > α2 > α3 = α4 > α1, for loreclezole α1 = α2 = α3 > α5 > α4, and for pentobarbital α4 = α5 = α2 > α1 = α3.

Footnotes

    • Received June 7, 2000.
    • Accepted January 26, 2001.
  • Send reprint requests to: Dr. Alison Smith, Department of Biochemistry, Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Rd., Harlow, Essex, CM20 2QR, UK. E-mail: alison_smith{at}merck.com

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Molecular Pharmacology: 59 (5)
Molecular Pharmacology
Vol. 59, Issue 5
1 May 2001
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Research ArticleArticle

Effect of α Subunit on Allosteric Modulation of Ion Channel Function in Stably Expressed Human Recombinant γ-Aminobutyric AcidA Receptors Determined Using36Cl Ion Flux

Alison J. Smith, Luanda Alder, Jonathan Silk, Charles Adkins, Alan E. Fletcher, Tim Scales, Julie Kerby, George Marshall, Keith A. Wafford, Ruth M. McKernan and John R. Atack
Molecular Pharmacology May 1, 2001, 59 (5) 1108-1118; DOI: https://doi.org/10.1124/mol.59.5.1108

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Research ArticleArticle

Effect of α Subunit on Allosteric Modulation of Ion Channel Function in Stably Expressed Human Recombinant γ-Aminobutyric AcidA Receptors Determined Using36Cl Ion Flux

Alison J. Smith, Luanda Alder, Jonathan Silk, Charles Adkins, Alan E. Fletcher, Tim Scales, Julie Kerby, George Marshall, Keith A. Wafford, Ruth M. McKernan and John R. Atack
Molecular Pharmacology May 1, 2001, 59 (5) 1108-1118; DOI: https://doi.org/10.1124/mol.59.5.1108
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