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

J Med Chem. 2009 May 14;52(9):2933-9. doi: 10.1021/jm9001007.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acylation
  • Animals
  • Cell Line
  • Dose-Response Relationship, Drug
  • Esterification
  • Humans
  • Mice
  • Phorbol Esters / chemistry*
  • Phorbol Esters / pharmacology*
  • Structure-Activity Relationship
  • TRPV Cation Channels / agonists
  • TRPV Cation Channels / metabolism*


  • Phorbol Esters
  • TRPV Cation Channels
  • Trpv4 protein, mouse