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

Heart failure (HF) is devastating disease with poor prognosis. Elevated sympathetic nervous system activity and outflow, leading to pathologic attenuation and desensitization of ß-adrenergic receptors (ß-ARs) signaling and responsiveness, are salient characteristic of HF progression. These pathologic effects on ß-AR signaling and HF progression occur in part due to Gßγ-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 Gßγ subunits to interact with multiple effector molecules that activate various signaling cascades involved in HF pathophysiology. Importantly, targeting Gßγ 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 Gßγ inhibitors that selectively block particular Gßγ functions by specifically targeting a Gßγ protein-protein interaction "hot spot." Here we describe their effects on Gßγ downstream signaling pathways, including their role in HF pathophysiology. We suggest a promising therapeutic role for small molecule inhibition of pathologic Gßγ signaling in the treatment of HF. This article is part of a special issue entitled "Key Signaling Molecules in Hypertrophy and Heart Failure."