A PI3Kγ mimetic peptide triggers CFTR gating, bronchodilation, and reduced inflammation in obstructive airway diseases

• DOI: 10.1126/scitranslmed.abl6328
• Publication Date: 2022-03-30T17:57:47Z
• Authors: Alessandra Ghigo; Alessandra Murabito; Valentina Sala; Anna Rita Pisano; Serena Bertolini; Ambra Gianotti; Emanuela Caci; Alessio Montresor; Aiswarya Premchandar; Flora Pirozzi; Kai Ren; Angela Della Sala; Marco Mergiotti; Wito Richter; Eyleen de Poel; Michaela Matthey; Sara Caldrer; Rosa A. Cardone; Federica Civiletti; Andrea Costamagna; Nancy L. Quinney; Cosmin Butnarasu; Sonja Visentin; Maria Rosaria Rug...; Simona Baroni; Simonetta Geninat...; Damien Ramel; Muriel Laffargue; Carlo G. Tocchetti; Renzo Levi; Marco Conti; Xiao-Yun Lu; Paola Melotti; Claudio Sorio; Virginia De Rose; Fabrizio Facchinetti; Vito Fanelli; Daniela Wenzel; Bernd K. Fleischmann; Marcus A. Mall; Jeffrey Beekman; Carlo Laudanna; Martina Gentzsch; Gergely L. Lukacs; Nicoletta Pedemonte; Emilio Hirsch
• Keywords: Cyclic adenosine monophosphate; Phosphoinositide 3-kinase

Cyclic adenosine 3′,5′-monophosphate (cAMP)–elevating agents, such as β 2 -adrenergic receptor (β -AR) agonists and phosphodiesterase (PDE) inhibitors, remain a mainstay in the treatment of obstructive respiratory diseases, conditions characterized by airway constriction, inflammation, mucus hypersecretion. However, their clinical use is limited unwanted side effects because unrestricted cAMP elevation airways distant organs. Here, we identified A-kinase anchoring protein phosphoinositide 3-kinase γ (PI3Kγ) critical regulator discrete signaling microdomain activated -ARs structural inflammatory cells. Displacement PI3Kγ-anchored pool kinase A (PKA) an inhaled, cell-permeable, PI3Kγ mimetic peptide (PI3Kγ MP) inhibited subcortical PDE4B PDE4D safely increased lungs, leading to smooth muscle relaxation reduced neutrophil infiltration murine model asthma. In human bronchial epithelial cells, MP induced unexpected PKA elevations restricted vicinity cystic fibrosis transmembrane conductance (CFTR), ion channel controlling hydration that mutated (CF). promoted phosphorylation wild-type CFTR on serine-737, triggering gating, rescued function F508del-CFTR, most prevalent CF mutant, enhancing existing modulators. These results unveil -AR/cAMP central contraction, immune cell activation, fluid secretion airways, suggesting for compartment-restricted, therapeutic chronic diseases.