Paroxetine Is a Direct Inhibitor of G Protein-Coupled Receptor Kinase 2 and Increases Myocardial Contractility

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• 作者：David M. Thal ; Kristoff T. Homan ; Jun Chen ; Emily K. Wu ; Patricia M. Hinkle ; Z. Maggie Huang ; J. Kurt Chuprun ; Jianliang Song ; Erhe Gao ; Joseph Y. Cheung ; Larry A. Sklar ; Walter J. Koch ; John J.G. Tesmer
• 刊名：ACS Chemical Biology
• 出版年：2012
• 出版时间：November 16, 2012
• 年：2012
• 卷：7
• 期：11
• 页码：1830-1839
• 全文大小：558K
• 年卷期：v.7,no.11(November 16, 2012)
• ISSN：1554-8937

文摘

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路paroxetine鈥揋尾纬 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.