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 agonistoccupied 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.".
All Science Journal Classification (ASJC) codes
- Molecular Biology
- Cardiology and Cardiovascular Medicine