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

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Modulation of the transient receptor potential vanilloid channel TRPV4 by 4alpha-phorbol esters: a structure-activity study. / Klausen, Thomas Kjaer; Pagani, Alberto; Minassi, Alberto; Ech-Chahad, Abdellah; Prenen, Jean; Owsianik, Grzegorz; Hoffmann, Else Kay; Pedersen, Stine Falsig; Appendino, Giovanni; Nilius, Bernd.

In: Journal of Medicinal Chemistry, Vol. 52, No. 9, 2009, p. 2933-9.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Klausen, TK, Pagani, A, Minassi, A, Ech-Chahad, A, Prenen, J, Owsianik, G, Hoffmann, EK, Pedersen, SF, Appendino, G & Nilius, B 2009, 'Modulation of the transient receptor potential vanilloid channel TRPV4 by 4alpha-phorbol esters: a structure-activity study', Journal of Medicinal Chemistry, vol. 52, no. 9, pp. 2933-9. https://doi.org/10.1021/jm9001007

APA

Klausen, T. K., Pagani, A., Minassi, A., Ech-Chahad, A., Prenen, J., Owsianik, G., Hoffmann, E. K., Pedersen, S. F., Appendino, G., & Nilius, B. (2009). Modulation of the transient receptor potential vanilloid channel TRPV4 by 4alpha-phorbol esters: a structure-activity study. Journal of Medicinal Chemistry, 52(9), 2933-9. https://doi.org/10.1021/jm9001007

Vancouver

Klausen TK, Pagani A, Minassi A, Ech-Chahad A, Prenen J, Owsianik G et al. Modulation of the transient receptor potential vanilloid channel TRPV4 by 4alpha-phorbol esters: a structure-activity study. Journal of Medicinal Chemistry. 2009;52(9):2933-9. https://doi.org/10.1021/jm9001007

Author

Klausen, Thomas Kjaer ; Pagani, Alberto ; Minassi, Alberto ; Ech-Chahad, Abdellah ; Prenen, Jean ; Owsianik, Grzegorz ; Hoffmann, Else Kay ; Pedersen, Stine Falsig ; Appendino, Giovanni ; Nilius, Bernd. / Modulation of the transient receptor potential vanilloid channel TRPV4 by 4alpha-phorbol esters: a structure-activity study. In: Journal of Medicinal Chemistry. 2009 ; Vol. 52, No. 9. pp. 2933-9.

Bibtex

@article{528037905cc911dea8de000ea68e967b,
title = "Modulation of the transient receptor potential vanilloid channel TRPV4 by 4alpha-phorbol esters: a structure-activity study",
abstract = "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.",
author = "Klausen, {Thomas Kjaer} and Alberto Pagani and Alberto Minassi and Abdellah Ech-Chahad and Jean Prenen and Grzegorz Owsianik and Hoffmann, {Else Kay} and Pedersen, {Stine Falsig} and Giovanni Appendino and Bernd Nilius",
note = "Keywords: Acylation; Animals; Cell Line; Dose-Response Relationship, Drug; Esterification; Humans; Mice; Phorbol Esters; Structure-Activity Relationship; TRPV Cation Channels",
year = "2009",
doi = "10.1021/jm9001007",
language = "English",
volume = "52",
pages = "2933--9",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "9",

}

RIS

TY - JOUR

T1 - Modulation of the transient receptor potential vanilloid channel TRPV4 by 4alpha-phorbol esters: a structure-activity study

AU - Klausen, Thomas Kjaer

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

N1 - Keywords: Acylation; Animals; Cell Line; Dose-Response Relationship, Drug; Esterification; Humans; Mice; Phorbol Esters; Structure-Activity Relationship; TRPV Cation Channels

PY - 2009

Y1 - 2009

N2 - 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.

AB - 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.

U2 - 10.1021/jm9001007

DO - 10.1021/jm9001007

M3 - Journal article

C2 - 19361196

VL - 52

SP - 2933

EP - 2939

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 9

ER -

ID: 12705450