Ginkgolide B and bilobalide block the pore of the 5-HT₃receptor at a location that overlaps the picrotoxin binding site.
Extracts from the Ginkgo biloba tree are widely used as herbal medicines, and include bilobalide (BB) and ginkgolides A and B (GA and GB). Here we examine their effects on human 5-HT(3)A and 5-HT(3)AB receptors, and compare these to the effects of the structurally related compounds picrotin (PTN) and picrotoxinin (PXN), the two components of picrotoxin (PTX), a known channel blocker of 5-HT(3), nACh and GABA(A) receptors. The compounds inhibited 5-HT-induced responses of 5-HT(3) receptors expressed in Xenopus oocytes, with IC(50) values of 470 μM (BB), 730 μM (GB), 470 μM (PTN), 11 μM (PXN) and >1mM (GA) in 5-HT(3)A receptors, and 3.1mM (BB), 3.9 mM (GB), 2.7 mM (PTN), 62 μM (PXN) and >1mM (GA) in 5-HT(3)AB receptors. Radioligand binding on receptors expressed in HEK 293 cells showed none of the compounds displaced the specific 5-HT(3) receptor antagonist [(3)H]granisetron, confirming that they do not act at the agonist binding site. Inhibition by GB at 5-HT(3)A receptors is weakly use-dependent, and recovery is activity dependent, indicating channel block. To further probe their site of action at 5-HT(3)A receptors, BB and GB were applied alone or in combination with PXN, and the results fitted to a mathematical model; the data revealed partially overlapping sites of action. We conclude that BB and GB block the channel of the 5-HT(3)A receptor. Thus these compounds have comparable, although less potent, behaviour than at some other Cys-loop receptors, demonstrating their actions are conserved across the family.
Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QW, UK.
Andrew J
AJ
Thompson
Gavin E
GE
Jarvis
Rujee K
RK
Duke
Graham A R
GA
Johnston
Sarah C R
SC
Lummis
D000818:Animals; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D003517:Cyclopentanes / Q000378:metabolism* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005663:Furans / Q000378:metabolism* / Q000494:pharmacology; D046934:Ginkgolides / Q000378:metabolism* / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D007783:Lactones / Q000378:metabolism* / Q000494:pharmacology; D010852:Picrotoxin / Q000378:metabolism*; D010936:Plant Extracts / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology; D044406:Receptors, Serotonin, 5-HT3 / Q000378:metabolism*; D058831:Serotonin 5-HT3 Receptor Antagonists / Q000302:isolation & purification / Q000378:metabolism* / Q000494:pharmacology; D014982:Xenopus laevis
D003517:Cyclopentanes; D005663:Furans; D046934:Ginkgolides; D007783:Lactones; D010852:Picrotoxin; D010936:Plant Extracts; D044406:Receptors, Serotonin, 5-HT3; D058831:Serotonin 5-HT3 Receptor Antagonists; C509409:HTR3A protein, human; C509410:HTR3B protein, human; C045856:ginkgolide B; C073710:bilobalide