Terpene trilactones from Ginkgo biloba are antagonists of cortical glycine and GABA(A) receptors

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Lidija Ivic, Tristan T J Sands, Nathan Fishkin, Koji Nakanishi, Arnold R Kriegstein, Kristian Strømgaard

Glycine and gamma-aminobutyric acid, type A (GABA(A)) receptors are members of the ligand-gated ion channel superfamily that mediate inhibitory synaptic transmission in the adult central nervous system. During development, the activation of these receptors leads to membrane depolarization. Ligands for the two receptors have important implications both in disease therapy and as pharmacological tools. Terpene trilactones (ginkgolides and bilobalide) are unique constituents of Ginkgo biloba extracts that have various effects on the central nervous system. We have investigated the relative potency of these compounds on glycine and GABA(A) receptors. We find that most of the ginkgolides are selective and potent antagonists of the glycine receptor. Bilobalide, the single major component in G. biloba extracts, also reduces glycine-induced currents, although to a lesser extent. Both ginkgolides and bilobalide inhibit GABA(A) receptors, with bilobalide demonstrating a more potent effect. Additionally, we provide evidence that open channels are required for glycine receptor inhibition by ginkgolides. Finally, we employ molecular modeling to elucidate the similarities and differences in the structure of the terpene trilactones to account for the pharmacological properties of these compounds and demonstrate a striking similarity between ginkgolides and picrotoxinin, a GABA(A) and recombinant glycine alpha-homomeric receptor antagonist.
Original languageEnglish
JournalJournal of Biological Chemistry
Volume278
Issue number49
Pages (from-to)49279-49285
Number of pages7
ISSN0021-9258
DOIs
Publication statusPublished - 5 Dec 2003
Externally publishedYes

    Research areas

  • Animals, Cerebral Cortex, Female, GABA-A Receptor Antagonists, Ginkgo biloba, Lactones, Picrotoxin, Pregnancy, Rats, Rats, Sprague-Dawley, Receptors, Glycine, Terpenes

ID: 45810094