Molecular determinants of ginkgolide binding in the glycine receptor pore

Journal of Neurochemistry
Rebecca HawthorneJoseph W Lynch

Abstract

Ginkgolides are potent blockers of the glycine receptor Cl- channel (GlyR) pore. We sought to identify their binding sites by comparing the effects of ginkgolides A, B and C and bilobalide on alpha1, alpha2, alpha1beta and alpha2beta GlyRs. Bilobalide sensitivity was drastically reduced by incorporation of the beta subunit. In contrast, the sensitivities to ginkgolides B and C were enhanced by beta subunit expression. However, ginkgolide A sensitivity was increased in the alpha2beta GlyR relative to the alpha2 GlyR but not in the alpha1beta GlyR relative to the alpha1 GlyR. We hypothesised that the subunit-specific differences were mediated by residue differences at the second transmembrane domain 2' and 6' pore-lining positions. The increased ginkgolide A sensitivity of the alpha2beta GlyR was transferred to the alpha1beta GlyR by the G2'A (alpha1 to alpha2 subunit) substitution. In addition, the alpha1 subunit T6'F mutation abolished inhibition by all ginkgolides. As the ginkgolides share closely related structures, their molecular interactions with pore-lining residues were amenable to mutant cycle analysis. This identified an interaction between the variable R2 position of the ginkgolides and the 2' residues of both alpha1 ...Continue Reading

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Citations

Apr 21, 2011·Molecular Pharmacology·A J ThompsonS C R Lummis
Dec 17, 2015·The Journal of Pharmacology and Experimental Therapeutics·Gavin E JarvisAndrew J Thompson
Jul 22, 2009·Journal of Neurochemistry·Xuebin ChenJoseph W Lynch
Jan 29, 2008·Journal of Neurochemistry·Judith A HeadsJoseph W Lynch
Aug 24, 2007·Journal of Neurochemistry·Zhe YangJoseph W Lynch
Nov 1, 2011·British Journal of Pharmacology·Robiul Islam, Joseph W Lynch
Mar 16, 2013·British Journal of Pharmacology·A J Thompson, S C R Lummis
Feb 22, 2013·British Journal of Pharmacology·Graham A R Johnston
Jul 26, 2012·Neuropharmacology·Shelley H HuangRujee K Duke
Aug 30, 2008·Neuropharmacology·Joseph W Lynch
Jan 3, 2012·Biophysical Journal·Mona AlqazzazSarah C R Lummis
Apr 5, 2007·The Journal of Biological Chemistry·Dian-Shi WangPascal Legendre
Oct 4, 2007·The Journal of Biological Chemistry·Stephan A PlessJoseph W Lynch
Nov 19, 2015·Frontiers in Molecular Neuroscience·Galyna MaleevaPiotr Bregestovski
Jan 1, 2015·SpringerPlus·Galyna MaleevaPiotr Bregestovski
Apr 13, 2019·Cell Death & Disease·Wendy P LoomisSusan L Fink

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