Beta-adrenergic signalling in neoplastic lung type 2 cells: glucocorticoid-dependent and -independent defects.
Tumorigenic mouse lung-derived type 2 cell lines have large reductions in both beta-adrenergic-stimulated cAMP production and ligand binding to beta-adrenergic receptors. These tumorigenic cells are also relatively insensitive to glucocorticoids. Because glucocorticoids regulate both beta-adrenergic receptor expression and receptor coupling to the stimulatory guanine nucleotide binding protein Gs interactions between the glucocorticoid and beta-adrenergic signalling systems were examined. This study demonstrates that beta-adrenergic ligand binding and agonist sensitivity are increased in a tumorigenic cell line stably expressing a normal glucocorticoid receptor transgene. However, although the transfected tumour cells and non-tumorigenic cells have similar amounts and affinities of beta-adrenergic agonist and antagonist binding, similar amounts of Gs subunits and similar forskolin-stimulated adenylyl cyclase activities, the former remain much less isoproterenol responsive. Competition binding studies demonstrate that tumour cell beta-adrenergic receptors have both high- and low-affinity agonist binding but are functionally uncoupled from Gs. This uncoupling may involve an alteration in Gs, as guanine nucleotides exhibit a reduced ability to stimulate adenylyl cyclase. Thus, some aspects of tumorigenic cell dysfunction in beta-adrenergic signalling can be ameliorated by interactions with the glucocorticoid pathway, but additional defects are also involved.
Droms
K A
KA
Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock 79430, USA.
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000032:analysis; D006165:Guanylyl Imidodiphosphate / Q000494:pharmacology; D006801:Humans; D020120:Iodocyanopindolol; D007545:Isoproterenol / Q000494:pharmacology; D008175:Lung Neoplasms / Q000503:physiopathology*; D051379:Mice; D010869:Pindolol / Q000031:analogs & derivatives / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000502:physiology*
D011943:Receptors, Adrenergic, beta; D005576:Colforsin; D006165:Guanylyl Imidodiphosphate; D003907:Dexamethasone; D020120:Iodocyanopindolol; D010869:Pindolol; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D007545:Isoproterenol