Phosphoinositide 3-kinase gamma–Protein kinase A protein–protein complex (PI3Kγ–PKA complex) (PI3Kγ–PKA complex)

The Phosphoinositide 3-kinase gamma–Protein kinase A (PI3Kγ–PKA) protein–protein complex is a critical regulatory assembly in cardiomyocytes where PI3Kγ serves as a scaffold, or A-kinase anchoring protein (AKAP), for PKA (Ghigo et al., 2012, Science). This interaction is independent of the lipid kinase activity of PI3Kγ and instead facilitates the localization of PKA to specific subcellular compartments to regulate cAMP-dependent signaling and the activity of phosphodiesterases (PDEs) (Perino et al., 2011, Molecular Cell). In healthy hearts, this complex maintains the balance of cAMP levels, which is essential for proper cardiac contractility and calcium handling. However, in chronic heart failure, the PI3Kγ–PKA interaction becomes a driver of pathological remodeling and contractile dysfunction due to the loss of cAMP compartmentation. Therapeutic strategies focus on disrupting this specific protein-protein interaction (PPI) to restore normal cAMP signaling without inhibiting the essential kinase activities of PI3Kγ or PKA globally. Preclinical studies using cell-permeable peptides or small-molecule disruptors have demonstrated that breaking this complex can improve cardiac output and reduce fibrosis in models of pressure overload (Ciraolo et al., 2014, Nature Communications). This makes the PI3Kγ–PKA complex a promising therapeutic target for cardiovascular diseases where cAMP signaling is impaired.

Other names

PI3Kgamma-PKA complexPIK3CG-PRKACA complexPI3Kγ-AKAP complexPhosphoinositide 3-kinase gamma-Protein Kinase A interaction

Disruption of the protein-protein interaction (PPI) between PI3Kγ and PKA to restore localized cAMP compartmentation and improve cardiac contractility.