Mixed antagonistic effects of the ginkgolides at recombinant human rho 1 GABA sub(C) receptors

• Published in: Neuropharmacology Vol. 63; no. 6; pp. 1127 - 1139
• Main Authors: Huang, Shelley H, Lewis, Trevor M, Lummis, Sarah CR, Thompson, Andrew J, Chebib, Mary, Johnston, Graham AR, Duke, Rujee K
• Format: Journal Article
• Language: English
• Published: 01-11-2012
• Subjects: Allosteric properties; Antagonists; diterpenes; gamma -Aminobutyric acid C receptors; Ginkgo biloba; ginkgolides; Kinetics; lactones; Oocytes
• ISSN: 0028-3908
• DOI: 10.1016/j.neuropharm.2012.06.067

The diterpene lactones of Ginkgo biloba, ginkgolides A, B and C are antagonists at a range of Cys-loop receptors. This study examined the effects of the ginkgolides at recombinant human rho 1 GABA sub(C) receptors expressed in Xenopus oocytes using two-electrode voltage clamp. The ginkgolides were moderately potent antagonists with IC sub(50s) in the mu M range. At 10 mu M, 30 mu M and 100 mu M, the ginkgolides caused rightward shifts of GABA dose-response curves and reduced maximal GABA responses, characteristic of noncompetitive antagonists, while the potencies showed a clear dependence on GABA concentration, indicating apparent competitive antagonism. This suggests that the ginkgolides exert a mixed-type antagonism at the rho 1 GABA sub(C) receptors. The ginkgolides did not exhibit any obvious use-dependent inhibition. Fitting of the data to a number of kinetic schemes suggests an allosteric inhibition as a possible mechanism of action of the ginkgolides which accounts for their inhibition of the responses without channel block or use-dependent inhibition. Kinetic modelling predicts that the ginkgolides exhibit saturation of antagonism at high concentrations of GABA, but this was only partially observed for ginkgolide B. It also suggests that there may be different binding sites in the closed and open states of the receptor, with a higher affinity for the receptor in the closed state.