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

Journal Article · Fri Aug 10 00:00:00 EDT 2012 · ACS Chemical Biology

DOI:https://doi.org/10.1021/cb3003013· OSTI ID:1056695

Thal, David M. ^[1]; Homan, Kristoff T. ^[1]; Chen, Jun ^[2]; Wu, Emily K. ^[1]; Hinkle, Patricia M. ^[3]; Huang, Z. Maggie ^[4]; Chuprun, J. Kurt ^[4]; Song, Jianliang ^[4]; Gao, Erhe ^[4]; Cheung, Joseph Y. ^[4]; Sklar, Larry A. ^[2]; Koch, Walter J. ^[4]; Tesmer, John J.G. ^[1]

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1. Univ. of Michigan, Ann Arbor, MI (United States)
2. Univ. of New Mexico Health Sciences Center, Albuquerque, NM (United States)
3. Univ. of Rochester Medical Center, Rochester, NY (United States)
4. Temple Univ. School of Medicine, Philadelphia, Pennsylvania (United States)

G protein-coupled receptor kinase 2 (GRK2) is a well-established therapeutic target for the treatment of heart failure. In this paper 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–Gβγ 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.

• Research Organization: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
• Sponsoring Organization: USDOE; National Institutes of Health (NIH)
• OSTI ID: 1056695
• Journal Information: ACS Chemical Biology, Vol. 7, Issue 11; ISSN 1554-8929
• Publisher: American Chemical Society
• Country of Publication: United States
• Language: ENGLISH