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

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KU Leuven, Department of Molecular Cell Biology, Laboratory Ion Channel Research, Campus Gasthuisberg, Herestraat 49, bus 802, Leuven, Belgium, Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche, Via Bovio 9, 28100 Novara, Italy, Department of Biology, Section of Cell and Developmental Biology, University of Copenhagen, 13 Universitetsparken, 2100 Copenhagen Ø, Denmark
* To whom correspondence should be addressed. For B.N.: phone, +32 16 34 5937; fax, 32 16 34 5991; E-mail, [email protected]. For G.A.: phone, +39 0321375744; fax, +39 0321375621; E-mail, [email protected]
†KU Leuven, Department of Molecular Cell Biology, Laboratory Ion Channel Research.
§Department of Biology, Section of Cell and Developmental Biology, University of Copenhagen.
‡Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche.
Cite this: J. Med. Chem. 2009, 52, 9, 2933–2939
Publication Date (Web):April 10, 2009
https://doi.org/10.1021/jm9001007
Copyright © 2009 American Chemical Society
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    Abstract

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    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.

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