TY - JOUR
T1 - Modulation of the transient receptor potential vanilloid channel TRPV4 by 4α-phorbol esters
T2 - A structure-activity study
AU - Klausen, Thomas Kjær
AU - Pagani, Alberto
AU - Minassi, Alberto
AU - Ech-Chahad, Abdellah
AU - Prenen, Jean
AU - Owsianik, Grzegorz
AU - Hoffmann, Else Kay
AU - Pedersen, Stine Falsig
AU - Appendino, Giovanni
AU - Nilius, Bernd
PY - 2009/5/14
Y1 - 2009/5/14
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=65649150431&partnerID=8YFLogxK
U2 - 10.1021/jm9001007
DO - 10.1021/jm9001007
M3 - Article
SN - 0022-2623
VL - 52
SP - 2933
EP - 2939
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 9
ER -