Taking the heart failure battle inside the cell: small molecule targeting of Gβγ subunits

J Mol Cell Cardiol. 2011 Oct;51(4):462-7. doi: 10.1016/j.yjmcc.2011.01.006. Epub 2011 Jan 21.


Heart failure (HF) is devastating disease with poor prognosis. Elevated sympathetic nervous system activity and outflow, leading to pathologic attenuation and desensitization of β-adrenergic receptors (β-ARs) signaling and responsiveness, are salient characteristic of HF progression. These pathologic effects on β-AR signaling and HF progression occur in part due to Gβγ-mediated signaling, including recruitment of receptor desensitizing kinases such as G-protein coupled receptor (GPCR) kinase 2 (GRK2) and phosphoinositide 3-kinase (PI3K), which subsequently phosphorylate agonist occupied GPCRs. Additionally, chronic GPCR signaling signals chronically dissociated Gβγ subunits to interact with multiple effector molecules that activate various signaling cascades involved in HF pathophysiology. Importantly, targeting Gβγ signaling with large peptide inhibitors has proven a promising therapeutic paradigm in the treatment of HF. We recently described an approach to identify small molecule Gβγ inhibitors that selectively block particular Gβγ functions by specifically targeting a Gβγ protein-protein interaction "hot spot." Here we describe their effects on Gβγ downstream signaling pathways, including their role in HF pathophysiology. We suggest a promising therapeutic role for small molecule inhibition of pathologic Gβγ signaling in the treatment of HF. This article is part of a special issue entitled "Key Signaling Molecules in Hypertrophy and Heart Failure."

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Adrenergic beta-Antagonists / therapeutic use
  • Animals
  • Cardiovascular Agents / therapeutic use
  • Drug Evaluation, Preclinical
  • GTP-Binding Protein beta Subunits / antagonists & inhibitors
  • GTP-Binding Protein beta Subunits / metabolism*
  • GTP-Binding Protein gamma Subunits / antagonists & inhibitors
  • GTP-Binding Protein gamma Subunits / metabolism*
  • Heart Failure / drug therapy*
  • Heart Failure / metabolism
  • Heart Failure / pathology
  • Humans
  • Molecular Targeted Therapy*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Receptors, Adrenergic, beta / metabolism
  • Signal Transduction / drug effects
  • beta-Adrenergic Receptor Kinases / antagonists & inhibitors
  • beta-Adrenergic Receptor Kinases / metabolism


  • Adrenergic beta-Antagonists
  • Cardiovascular Agents
  • GTP-Binding Protein beta Subunits
  • GTP-Binding Protein gamma Subunits
  • Phosphoinositide-3 Kinase Inhibitors
  • Receptors, Adrenergic, beta
  • beta-Adrenergic Receptor Kinases