Ginkgolide B and bilobalide block the pore of the 5-HT3 receptor at a location that overlaps the picrotoxin binding site
Data(s) |
01/02/2011
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Resumo |
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. |
Identificador | |
Idioma(s) |
eng |
Direitos |
info:eu-repo/semantics/restrictedAccess |
Fonte |
Thompson , A J , Jarvis , G , Duke , R K , Johnston , G A R & Lummis , S C R 2011 , ' Ginkgolide B and bilobalide block the pore of the 5-HT3 receptor at a location that overlaps the picrotoxin binding site ' Neuropharmacology , vol 60 , no. 2-3 , pp. 488-495 . DOI: 10.1016/j.neuropharm.2010.11.003 |
Palavras-Chave | #/dk/atira/pure/subjectarea/asjc/2800/2804 #Cellular and Molecular Neuroscience #/dk/atira/pure/subjectarea/asjc/3000/3004 #Pharmacology |
Tipo |
article |