LAUSR

Cyclic adenosine 3′,5′-monophosphate (cAMP)–elevating agents, such as β2-adrenergic receptor (β2-AR) agonists and phosphodiesterase (PDE) inhibitors, remain a mainstay in the treatment of obstructive respiratory diseases, conditions characterized by airway constriction, inflammation, and mucus hypersecretion. However, their clinical use is limited by unwanted side effects because of unrestricted cAMP elevation in the airways and in distant organs. Here, we identified the A-kinase anchoring protein phosphoinositide 3-kinase γ (PI3Kγ) as a critical regulator of a discrete cAMP signaling microdomain activated by β2-ARs in airway structural and inflammatory cells. Displacement of the PI3Kγ-anchored pool of protein kinase A (PKA) by an inhaled, cell-permeable, PI3Kγ mimetic peptide (PI3Kγ MP) inhibited a pool of subcortical PDE4B and PDE4D and safely increased cAMP in the lungs, leading to airway smooth muscle relaxation and reduced neutrophil infiltration in a murine model of asthma. In human bronchial epithelial cells, PI3Kγ MP induced unexpected cAMP and PKA elevations restricted to the vicinity of the cystic fibrosis transmembrane conductance regulator (CFTR), the ion channel controlling mucus hydration that is mutated in cystic fibrosis (CF). PI3Kγ MP promoted the phosphorylation of wild-type CFTR on serine-737, triggering channel gating, and rescued the function of F508del-CFTR, the most prevalent CF mutant, by enhancing the effects of existing CFTR modulators. These results unveil PI3Kγ as the regulator of a β2-AR/cAMP microdomain central to smooth muscle contraction, immune cell activation, and epithelial fluid secretion in the airways, suggesting the use of a PI3Kγ MP for compartment-restricted, therapeutic cAMP elevation in chronic obstructive respiratory diseases. Description A PI3Kγ mimetic peptide enhances airway cAMP, dilates bronchia, reduces inflammation, and promotes chloride secretion in obstructive airway diseases. PI3K-ing a mimetic Increasing cyclic adenosine monophosphate (cAMP) in the airways of patients with obstructive lung diseases can reduce airway inflammation and constriction. However, current therapies can induce treatment-limiting systemic side effects. Here, Ghigo and colleagues found that phosphoinositide 3-kinase γ (PI3Kγ) negatively regulated the β2-adrenergic receptor signaling pathway to decrease cAMP. They created a PI3Kγ mimetic peptide that increased local cAMP concentrations and, when administered intratracheally in a mouse model of asthma, induced airway relaxation and reduced neutrophil infiltration. Further, in airway epithelial cells from patients with cystic fibrosis, it triggered gating of the cystic fibrosis transmembrane conductance regulator (CFTR) channel and enhanced the effects of CFTR modulators, suggesting that the PI3Kγ mimetic peptide may be used to treat obstructive lung diseases in humans.