Modulation of the Transient Receptor Potential Vanilloid Channel TRPV4 by 4α-Phorbol Esters: A Structure−Activity Study

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• 作者：Thomas Kjæ ; r Klausen ; Alberto Pagani ; Alberto Minassi ; Abdellah Ech-Chahad ; Jean Prenen ; Grzegorz Owsianik ; Else Kay Hoffmann ; Stine Falsig Pedersen ; Giovanni Appendino ; Bernd Nilius
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：May 14, 2009
• 年：2009
• 卷：52
• 期：9
• 页码：2933-2939
• 全文大小：240K
• 年卷期：v.52,no.9(May 14, 2009)
• ISSN：1520-4804

文摘

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.