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

ACS Chem Biol. 2012 Nov 16;7(11):1830-9. doi: 10.1021/cb3003013. Epub 2012 Aug 21.

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-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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Catalytic Domain / drug effects
  • Cells, Cultured
  • G-Protein-Coupled Receptor Kinase 2 / antagonists & inhibitors*
  • G-Protein-Coupled Receptor Kinase 2 / chemistry
  • G-Protein-Coupled Receptor Kinase 2 / metabolism
  • Heart / drug effects*
  • Heart / physiology
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Models, Molecular
  • Myocardial Contraction / drug effects*
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / enzymology
  • Paroxetine / pharmacology*
  • Phosphorylation / drug effects
  • Protein Conformation / drug effects
  • Protein Structure, Tertiary / drug effects
  • Serotonin Uptake Inhibitors / pharmacology*
  • Thyrotropin-Releasing Hormone / metabolism

Substances

  • Serotonin Uptake Inhibitors
  • Paroxetine
  • Thyrotropin-Releasing Hormone
  • G-Protein-Coupled Receptor Kinase 2