Protein kinase A-Iα regulates Na,K-ATPase endocytosis in alveolar epithelial cells exposed to high CO(2) concentrations.
Elevated concentrations of CO2 (hypercapnia) lead to alveolar epithelial dysfunction by promoting Na,K-ATPase endocytosis. In the present report, we investigated whether the CO2/HCO3(-) activated soluble adenylyl cyclase (sAC) regulates this process. We found that hypercapnia increased the production of cyclic adenosine monophosphate (cAMP) and stimulated protein kinase A (PKA) activity via sAC, which was necessary for Na,K-ATPase endocytosis. During hypercapnia, cAMP was mainly produced in specific microdomains in the proximity of the plasma membrane, leading to PKA Type Iα activation. In alveolar epithelial cells exposed to high CO2 concentrations, PKA Type Iα regulated the time-dependent phosphorylation of the actin cytoskeleton component α-adducin at serine 726. Cells expressing small hairpin RNA for PKAc, dominant-negative PKA Type Iα, small interfering RNA for α-adducin, and α-adducin with serine 726 mutated to alanine prevented Na,K-ATPase endocytosis. In conclusion, we provide evidence for a new mechanism by which hypercapnia via sAC, cAMP, PKA Type Iα, and α-adducin regulates Na,K-ATPase endocytosis in alveolar epithelial cells.
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. e-lecuona@northwestern.edu
Emilia
E
Lecuona
Haiying
H
Sun
Jiwang
J
Chen
Humberto E
HE
Trejo
Margaret A
MA
Baker
Jacob I
JI
Sznajder
D000262:Adenylyl Cyclases / Q000378:metabolism; D056809:Alveolar Epithelial Cells / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology; D000818:Animals; D002148:Calmodulin-Binding Proteins / Q000378:metabolism; D002245:Carbon Dioxide / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000201:enzymology; D000242:Cyclic AMP / Q000378:metabolism; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / Q000502:physiology*; D004705:Endocytosis; D006801:Humans; D006935:Hypercapnia / Q000201:enzymology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D051381:Rats; D017207:Rats, Sprague-Dawley; D015290:Second Messenger Systems; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*; D000099291:Adducins
D000262:Adenylyl Cyclases; D002148:Calmodulin-Binding Proteins; D002245:Carbon Dioxide; D000242:Cyclic AMP; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D011493:Protein Kinase C; D000254:Sodium-Potassium-Exchanging ATPase; D000099291:Adducins; C517834:PRKAR1A protein, human; C499076:ATP1A1 protein, human