Paroxetine is a direct inhibitor of G protein-coupled receptor kinase 2 and increases myocardial contractility

David Thal, Kristoff T Homan, Jun Chen, Emily Wu, Patricia M Hinkle, Zheng Maggie Huang, J Kurt Chuprun, Jianliang Song, Erhe Gao, Joseph Cheung, Larry A Sklar, Walter Koch, John Joseph Grubb Tesmer

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Abstract

G protein-coupled receptor kinase 2 (GRK2) is a well-established therapeutic target for the treatment of heart failure. Herein we identify the selective serotonin reuptake inhibitor (SSRI) paroxetine as a selective inhibitor of GRK2 activity both in vitro and in living cells. In the crystal structure of the GRK2?paroxetine-G?? complex, paroxetine binds in the active site of GRK2 and stabilizes the kinase domain in a novel conformation in which a unique regulatory loop forms part of the ligand binding site. Isolated cardiomyocytes show increased isoproterenol-induced shortening and contraction amplitude in the presence of paroxetine, and pretreatment of mice with paroxetine before isoproterenol significantly increases left ventricular inotropic reserve in vivo with no significant effect on heart rate. Neither is observed in the presence of the SSRI fluoxetine. Our structural and functional results validate a widely available drug as a selective chemical probe for GRK2 and represent a starting point for the rational design of more potent and specific GRK2 inhibitors.
Original languageEnglish
Pages (from-to)1830 - 1839
Number of pages10
JournalACS Chemical Biology
Volume7
Issue number11
DOIs
Publication statusPublished - 2012
Externally publishedYes

Cite this

Thal, D., Homan, K. T., Chen, J., Wu, E., Hinkle, P. M., Huang, Z. M., ... Tesmer, J. J. G. (2012). Paroxetine is a direct inhibitor of G protein-coupled receptor kinase 2 and increases myocardial contractility. ACS Chemical Biology, 7(11), 1830 - 1839. https://doi.org/10.1021/cb3003013
Thal, David ; Homan, Kristoff T ; Chen, Jun ; Wu, Emily ; Hinkle, Patricia M ; Huang, Zheng Maggie ; Chuprun, J Kurt ; Song, Jianliang ; Gao, Erhe ; Cheung, Joseph ; Sklar, Larry A ; Koch, Walter ; Tesmer, John Joseph Grubb. / Paroxetine is a direct inhibitor of G protein-coupled receptor kinase 2 and increases myocardial contractility. In: ACS Chemical Biology. 2012 ; Vol. 7, No. 11. pp. 1830 - 1839.
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title = "Paroxetine is a direct inhibitor of G protein-coupled receptor kinase 2 and increases myocardial contractility",
abstract = "G protein-coupled receptor kinase 2 (GRK2) is a well-established therapeutic target for the treatment of heart failure. Herein we identify the selective serotonin reuptake inhibitor (SSRI) paroxetine as a selective inhibitor of GRK2 activity both in vitro and in living cells. In the crystal structure of the GRK2?paroxetine-G?? complex, paroxetine binds in the active site of GRK2 and stabilizes the kinase domain in a novel conformation in which a unique regulatory loop forms part of the ligand binding site. Isolated cardiomyocytes show increased isoproterenol-induced shortening and contraction amplitude in the presence of paroxetine, and pretreatment of mice with paroxetine before isoproterenol significantly increases left ventricular inotropic reserve in vivo with no significant effect on heart rate. Neither is observed in the presence of the SSRI fluoxetine. Our structural and functional results validate a widely available drug as a selective chemical probe for GRK2 and represent a starting point for the rational design of more potent and specific GRK2 inhibitors.",
author = "David Thal and Homan, {Kristoff T} and Jun Chen and Emily Wu and Hinkle, {Patricia M} and Huang, {Zheng Maggie} and Chuprun, {J Kurt} and Jianliang Song and Erhe Gao and Joseph Cheung and Sklar, {Larry A} and Walter Koch and Tesmer, {John Joseph Grubb}",
year = "2012",
doi = "10.1021/cb3003013",
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Thal, D, Homan, KT, Chen, J, Wu, E, Hinkle, PM, Huang, ZM, Chuprun, JK, Song, J, Gao, E, Cheung, J, Sklar, LA, Koch, W & Tesmer, JJG 2012, 'Paroxetine is a direct inhibitor of G protein-coupled receptor kinase 2 and increases myocardial contractility', ACS Chemical Biology, vol. 7, no. 11, pp. 1830 - 1839. https://doi.org/10.1021/cb3003013

Paroxetine is a direct inhibitor of G protein-coupled receptor kinase 2 and increases myocardial contractility. / Thal, David; Homan, Kristoff T; Chen, Jun; Wu, Emily; Hinkle, Patricia M; Huang, Zheng Maggie; Chuprun, J Kurt; Song, Jianliang; Gao, Erhe; Cheung, Joseph; Sklar, Larry A; Koch, Walter; Tesmer, John Joseph Grubb.

In: ACS Chemical Biology, Vol. 7, No. 11, 2012, p. 1830 - 1839.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Paroxetine is a direct inhibitor of G protein-coupled receptor kinase 2 and increases myocardial contractility

AU - Thal, David

AU - Homan, Kristoff T

AU - Chen, Jun

AU - Wu, Emily

AU - Hinkle, Patricia M

AU - Huang, Zheng Maggie

AU - Chuprun, J Kurt

AU - Song, Jianliang

AU - Gao, Erhe

AU - Cheung, Joseph

AU - Sklar, Larry A

AU - Koch, Walter

AU - Tesmer, John Joseph Grubb

PY - 2012

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AB - G protein-coupled receptor kinase 2 (GRK2) is a well-established therapeutic target for the treatment of heart failure. Herein we identify the selective serotonin reuptake inhibitor (SSRI) paroxetine as a selective inhibitor of GRK2 activity both in vitro and in living cells. In the crystal structure of the GRK2?paroxetine-G?? complex, paroxetine binds in the active site of GRK2 and stabilizes the kinase domain in a novel conformation in which a unique regulatory loop forms part of the ligand binding site. Isolated cardiomyocytes show increased isoproterenol-induced shortening and contraction amplitude in the presence of paroxetine, and pretreatment of mice with paroxetine before isoproterenol significantly increases left ventricular inotropic reserve in vivo with no significant effect on heart rate. Neither is observed in the presence of the SSRI fluoxetine. Our structural and functional results validate a widely available drug as a selective chemical probe for GRK2 and represent a starting point for the rational design of more potent and specific GRK2 inhibitors.

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