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

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

The mechanism of activation of the transient receptor potential vanilloid 4 (TRPV4) channel by 4alpha-phorbol esters was investigated by combining information from chemical modification of 4alpha-phorbol-didecanoate (4alpha-PDD, 2a), site-directed mutagenesis, Ca(2+) imaging, and electrophysiology. Binding of 4alpha-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 Ca(2+)-dependence of the TRPV4 response. Taken together, our results show that 4alpha-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.
Original languageEnglish
JournalJournal of Medicinal Chemistry
Issue number9
Pages (from-to)2933-9
Number of pages6
StatePublished - 2009

Bibliographical note

Keywords: Acylation; Animals; Cell Line; Dose-Response Relationship, Drug; Esterification; Humans; Mice; Phorbol Esters; Structure-Activity Relationship; TRPV Cation Channels

ID: 12705450