Ginkgolide B and bilobalide block the pore of the 5-HT3 receptor at a location that overlaps the picrotoxin binding site

NEUROPHARMACOLOGY

卷:60

Article

Thompson, Andrew J.¹  Jarvis, Gavin E.¹  Duke, Rujee K.²  Johnston, Graham A. R.²  Lummis, Sarah C. R.¹ 

[1] Univ Cambridge, Dept Biochem, Cambridge CB2 1QW, England

[2] Univ Sydney, Dept Pharmacol, Sydney, NSW 2006, Australia

关键词: Serotonin;    Cys-loop;    Picrotoxin;    Antagonist;    Channel;   

DOI  :  10.1016/j.neuropharm.2010.11.003

来源: Elsevier

【 摘 要 】

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-HT3, nACh and GABA(A) receptors. The compounds inhibited 5-HT-induced responses of 5-HT3 receptors expressed in Xenopus oocytes, with IC50 values of 470 mu M (BB), 730 mu M (GB), 470 mu M (PTN), 11 mu M (PXN) and > 1 mM (GA) in 5-HT(3)A receptors, and 3.1 mM (BB), 3.9 mM (GB), 2.7 mM (PTN), 62 mu M (PXN) and > 1 mM (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-HT3 receptor antagonist [H-3]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. (C) 2010 Published by Elsevier Ltd.

【 授权许可】

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