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Potency of GABA at human recombinant GABAA receptors expressed in Xenopus oocytes: a mini review

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Abstract

GABAA receptors are members of the ligand-gated ion channel superfamily that mediate inhibitory neurotransmission in the central nervous system. They are thought to be composed of 2 alpha (α), 2 beta (β) subunits and one other such as a gamma (γ) or delta (δ) subunit. The potency of GABA is influenced by the subunit composition. However, there are no reported systematic studies that evaluate GABA potency on a comprehensive number of subunit combinations expressed in Xenopus oocytes, despite the wide use of this heterologous expression system in structure–function studies and drug discovery. Thus, the aim of this study was to conduct a systematic characterization of the potency of GABA at 43 human recombinant GABAA receptor combinations expressed in Xenopus oocytes using the two-electrode voltage clamp technique. The results show that the α-subunits and to a lesser extent, the β-subunits influence GABA potency. Of the binary and ternary combinations with and without the γ2L subunit, the α6/γ2L-containing receptors were the most sensitive to GABA, while the β2- or β3-subunit conferred higher sensitivity to GABA than receptors containing the β1-subunit with the exception of the α2β1γ2L and α6β1γ2L subtypes. Of the δ-subunit containing GABAA receptors, α4/δ-containing GABAA receptors displayed highest GABA sensitivity, with mid-nanomolar concentrations activating α4β1δ and α4β3δ receptors. At α4β2δ, GABA had low micromolar activity.

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Acknowledgments

We are grateful to Dr. Paul Whiting (Merck, Sharpe and Dohme Research Laboratories, Harlow, UK) and Dr. Bjarke Ebert (H. Lundbeck A/S Valby, Denmark) for the gift of cDNA for GABAA subunits. We are very grateful to the Department of Pharmacology, The University of Sydney, for managing and maintaining the Xenopus laevis colony. MC acknowledges travel support from the Drug Research Academy, the Faculty of Pharmaceutical Sciences, The University of Copenhagen, Denmark, and the Australian Academy of Sciences. PW acknowledges support from the Alfred Benzon Foundation, Denmark. NK acknowledges The University of Malakand, Pakistan (Faculty Development Programme Scholarship) and the John Lamberton Scholarship. The funding sources solely provided financial support and were not involved in any part of the conduct of the research.

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Authors and Affiliations

  1. Faculty of Pharmacy A15, University of Sydney, Sydney, NSW, 2006, Australia

    Nasiara Karim, Nathan Absalom, Graham A. R. Johnston, Jane R. Hanrahan & Mary Chebib

  2. Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2 Universitetsparken, DK-2100, Copenhagen, Denmark

    Petrine Wellendorph

  3. Department of Pharmacy, University of Malakand, Chakdara, Dir (Lower), KPK, Pakistan

    Nasiara Karim

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  1. Nasiara Karim
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  2. Petrine Wellendorph
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  3. Nathan Absalom
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  5. Jane R. Hanrahan
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  6. Mary Chebib
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Correspondence to Mary Chebib.

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Karim, N., Wellendorph, P., Absalom, N. et al. Potency of GABA at human recombinant GABAA receptors expressed in Xenopus oocytes: a mini review. Amino Acids 44, 1139–1149 (2013). https://doi.org/10.1007/s00726-012-1456-y

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