Modulation of the transient receptor potential vanilloid channel TRPV4 by 4α-phorbol esters: A structure-activity study

Thomas Kjær Klausen, Alberto Pagani, Alberto Minassi, Abdellah Ech-Chahad, Jean Prenen, Grzegorz Owsianik, Else Kay Hoffmann, Stine Falsig Pedersen, Giovanni Appendino, Bernd Nilius

Risultato della ricerca: Contributo su rivistaArticolo in rivistapeer review

Abstract

The mechanism of activation of the transient receptor potential vanilloid 4 (TRPV4) channel by 4α-phorbol esters was investigated by combining information from chemical modification of 4α-phorbol-didecanoate (4α-PDD, 2a), site-directed mutagenesis, Ca2+ imaging, and electrophysiology. Binding of 4α-phorbol esters occurs in a loop in the TM3-TM4 domain of TRPV4 that is analogous to the capsaicin binding site of TRPV1, and the ester decoration of ring C and the A,B ring junction are critical for activity. The lipophilic ester groups on ring C serve mainly as a steering element, affecting the orientation of the diterpenoid core into the ligand binding pocket, while the nature of the A,B ring junction plays an essential role in the Ca2+-dependence of the TRPV4 response. Taken together, our results show that 4α-phorbol is a useful template to investigate the molecular details of TRPV4 activation by small molecules and obtain information for the rational design of structurally simpler ligands for this ion channel.

Lingua originaleInglese
pagine (da-a)2933-2939
Numero di pagine7
RivistaJournal of Medicinal Chemistry
Volume52
Numero di pubblicazione9
DOI
Stato di pubblicazionePubblicato - 14 mag 2009

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