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Modulation of Ionotropic GABA Receptors by 6-Methoxyflavanone and 6-Methoxyflavone

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Abstract

We evaluated the effects of 6-methoxyflavanone and 6-methoxyflavone on wild-type α1/α2β2γ2L GABAA and ρ1 GABAC receptors and on mutant ρ1I307S, ρ1W328 M, ρ1I307S/W328 M GABAC receptors expressed in Xenopus oocytes using two-electrode voltage clamp and radioligand binding. 6-Methoxyflavanone and 6-methoxyflavone act as a flumazenil-insensitive positive allosteric modulator of GABA responses at human recombinant α1β2γ2L and α2β2γ2L GABAA receptors. However, unlike 6-methoxyflavone, 6-methoxyflavanone was relatively inactive at α1β2 GABAA receptors. 6-Methoxyflavanone inhibited [3H]-flunitrazepam binding to rat brain membranes. Both flavonoids were found to be inactive as modulators at ρ1, ρ1I307S and ρ1W328 M GABA receptors but acted as positive allosteric modulators of GABA at the benzodiazepine sensitive ρ1I307S/W328 M GABA receptors. This double mutant retains ρ1 properties of being insensitive to bicuculline and antagonised by TPMPA and THIP. Additionally, 6-methoxyflavanone was also a partial agonist at ρ1W328 M GABA receptors. The relative inactivity of 6-methoxyflavanone at α1β2 GABAA receptors and it’s partial agonist action at ρ1W328 M GABA receptors suggest that it exhibits a unique profile not matched by other flavonoids.

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Abbreviations

DMSO:

Dimethyl sulfoxide

GABA:

γ-Amino butyric acid

GABAA :

γ-Amino butyric acid-A receptor

THIP:

4,5,6,7-Tetrahydroisoxazolo[5,4-c]pyridin-3-ol

TPMPA:

(1,2,5,6-Tetrahydropyridin-4-yl)methylphosphinic acid

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Acknowledgments

We are grateful to Dr Paul Whiting (Merck, Sharpe and Dohme Research Laboratories, Harlow, UK) for the gift of human α1, α2, β2 and γ2L DNA, Dr George Uhl (National Institute for Drug Abuse, Baltimore, MD, USA) for the gift of human ρ1 DNA, Professor Jeremy Lambert (University of Dundee, Dundee, UK) for the gift of human ρ1I307S, ρ1W328M and ρ1W328M/I307S DNA. THIP was a gift from Prof. Povl Krogsgaard-Larsen (Copenhagen). We are also grateful to all those who performed the surgery to provide the oocytes. This work was funded by a grant from the National Health and Medical Research Council (NH&MRC). BJH was supported by an Australian Postgraduate Award and the John Lamberton Scholarship. NK acknowledges funding from The University of Malakand, Pakistan (Faculty Development Programme Scholarship) and the John Lamberton Scholarship.

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The authors state no conflict of interest.

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Authors and Affiliations

  1. Department of Pharmacology, The University of Sydney, Sydney, NSW, 2006, Australia

    Belinda J. Hall & Graham A. R. Johnston

  2. Faculty of Pharmacy, The University of Sydney, Sydney, NSW, 2006, Australia

    Nasiara Karim, Mary Chebib & Jane R. Hanrahan

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  1. Belinda J. Hall
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  2. Nasiara Karim
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  3. Mary Chebib
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  4. Graham A. R. Johnston
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Correspondence to Jane R. Hanrahan.

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Special Issue: In Honor of Richard Olsen.

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Hall, B.J., Karim, N., Chebib, M. et al. Modulation of Ionotropic GABA Receptors by 6-Methoxyflavanone and 6-Methoxyflavone. Neurochem Res 39, 1068–1078 (2014). https://doi.org/10.1007/s11064-013-1157-2

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  • DOI: https://doi.org/10.1007/s11064-013-1157-2

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