Beta-adrenergic regulation of amiloride-sensitive lung sodium channels.
We investigated the mechanism by which cAMP increases sodium transport in lung epithelial cells. Alveolar type II (ATII) cells have two types of amiloride-sensitive, cation channels: a nonselective cation channel (NSC) and a highly selective channel (HSC). Exposure of ATII cells to cAMP, beta-adrenergic agonists, or other agents that increase adenylyl cyclase activity increased activity of both channel types, albeit by different mechanisms. NSC open probability (P(o)) increased severalfold when exposed to terbutaline, isoproterenol, forskolin, or cAMP analogs without any change in NSC number. In contrast, terbutaline increased HSC number with no significant change in HSC P(o). For both channels, the effect of terbutaline was blocked by propranolol and H-89, suggesting a protein kinase A (PKA) requirement for beta-adrenergic-induced changes in channel activity. Terbutaline increased cAMP levels in ATII cells, but intracellular calcium also increased. Calcium sequestration with BAPTA blocked beta-adrenergic-induced increases in NSC P(o) but did not alter HSC activity. These observations suggest that beta-adrenergic stimulation increases intracellular cAMP and activates PKA. PKA increases HSC number and increases intracellular calcium. The increase in calcium increases NSC P(o). Thus increased cAMP levels are likely to increase lung sodium transport regardless of which channel type is present.
Chen
Xi-Juan
XJ
Department of Pediatrics, Emory University School of Medicine, 2040 Ridgewood Drive NE, Atlanta, GA 30322, USA.
Eaton
Douglas C
DC
Jain
Lucky
L
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D017920:Antiporters / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004232:Diuretics / Q000494:pharmacology; D004533:Egtazic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D015633:Extravascular Lung Water / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D011650:Pulmonary Alveoli / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels / Q000378:metabolism*; D013449:Sulfonamides; D013726:Terbutaline / Q000494:pharmacology*
D000318:Adrenergic beta-Agonists; D017920:Antiporters; D002614:Chelating Agents; D004232:Diuretics; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D011943:Receptors, Adrenergic, beta; D015222:Sodium Channels; D013449:Sulfonamides; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D005576:Colforsin; D004533:Egtazic Acid; D000584:Amiloride; D012964:Sodium; D000242:Cyclic AMP; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases; D007545:Isoproterenol; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; D013726:Terbutaline; D002118:Calcium