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

Abstract

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.

• 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 Ruggiero, Simona Baroni, Simonetta Geninatti Crich, 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
• Journal: Science translational medicine (Sci Transl Med) Vol. 14 Issue 638 Pg. eabl6328 (03 30 2022) ISSN: 1946-6242 [Electronic] United States
• PMID: 35353541 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• CFTR protein, human
• Peptides
• Cystic Fibrosis Transmembrane Conductance Regulator
• Class Ib Phosphatidylinositol 3-Kinase
• PIK3CG protein, human
• Phosphatidylinositol 3-Kinase
• Pik3cg protein, mouse

Topics

• Animals
• Class Ib Phosphatidylinositol 3-Kinase
• Cystic Fibrosis Transmembrane Conductance Regulator (metabolism)
• Humans
• Inflammation
• Mice
• Peptides (metabolism)
• Phosphatidylinositol 3-Kinase (metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)