Phosphoinositide 3-kinase gamma-A-kinase anchoring protein interface (PI3Kγ-AKAP interface)

The PI3Kγ AKAP interface refers to the protein-protein interaction between the catalytic subunit of phosphoinositide 3-kinase gamma (p110γ) and the regulatory subunits (specifically RIIα) of protein kinase A (PKA) [NIH, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3153153/]. In this context, PI3Kγ functions as a non-canonical A-kinase anchoring protein (AKAP) that scaffolds PKA and phosphodiesterases (PDE3B and PDE4) into a signaling microdomain to regulate local cAMP levels [NIH, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754836/]. In diseases like heart failure and chronic obstructive pulmonary disease, this complex is often dysregulated, leading to impaired cAMP signaling and receptor downregulation [NIH, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3153153/]. Therapeutic strategies focus on using disruptor peptides, such as DRI-Pep #20 or PI3Kγ mimetic peptides, to uncouple PKA from PI3Kγ, thereby restoring local cAMP concentrations and improving physiological functions like cardiac contractility and airway relaxation [NIH, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10927144/]. This target is particularly attractive because it allows for compartment-specific signaling modulation without affecting the global kinase activity of PI3Kγ or other PKA-AKAP complexes [ResearchGate, https://www.researchgate.net/publication/384784444_Unlocking_cAMP_modulation_a_new_peptide_targeting_PI3Kg_in_pulmonary_cells]. By targeting the scaffold function rather than the enzymatic activity, these drugs aim to achieve higher specificity and fewer side effects compared to traditional kinase inhibitors.

Other names

PI3Kγ-PKA interfacep110γ-PKA interaction sitePI3Kγ-AKAP complexPI3Kγ-RIIα interfacePhosphoinositide 3-kinase gamma-Protein kinase A interface

Disruption of the protein-protein interaction between PI3Kγ and PKA regulatory subunits to restore local cAMP signaling microdomains and prevent β-adrenergic receptor downregulation [NIH, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3153153/].