Enhancement of beta-adrenergic cAMP-signaling by the mineralocorticoid receptor.
We examined the modulation of adrenergic cell signaling by the human mineralocorticoid receptor (hMR) in renal cell lines (RC.SV3) stably transfected with full-length (M cells) or truncated hMR. Isoproterenol time-dependently increased intracellular cAMP formation, which was up to six-fold higher in M cells than in parental RC.SV3 cells. Incubation of cells with aldosterone or spironolactone for 24h neither changed the basal nor the isoproterenol-stimulated cAMP level in both cell lines, while inhibitor studies revealed that those effects are mediated by the beta(2)-adrenergic receptor. Expression of stimulatory G protein alpha was increased and that of G protein receptor coupled kinase 3 (GRK3) was reduced by hMR. Deletion studies of cells stably transfected with truncated hMR indicated that the N-terminal and the DNA binding domains of hMR are essential for enhancement of the catecholamine signal transduction pathway. In conclusion, our findings suggest a novel interplay between cAMP and MR signaling pathways.
Christ
Michael
M
Institute of Clinical Pharmacology, Faculty of Clinical Medicine Mannheim, University of Heidelberg, Theodor Kutzer Ufer 1, D-68135 Mannheim, Germany. christ_michael@yahoo.de
Wehling
Martin
M
Kirsch
Elke
E
Viengchareun
Say
S
Zennaro
Maria-Christina
MC
Lombès
Marc
M
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000450:Aldosterone / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism*; D054770:G-Protein-Coupled Receptor Kinase 3; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D007668:Kidney / Q000166:cytology; D010446:Peptide Fragments / Q000235:genetics / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011817:Rabbits; D020239:Receptor Cross-Talk; D018343:Receptors, Adrenergic, beta-2 / Q000502:physiology*; D018161:Receptors, Mineralocorticoid / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D013148:Spironolactone / Q000494:pharmacology; D014162:Transfection
D000318:Adrenergic beta-Agonists; D044385:GTP-Binding Protein alpha Subunits; D010446:Peptide Fragments; D018343:Receptors, Adrenergic, beta-2; D018161:Receptors, Mineralocorticoid; D013148:Spironolactone; D000450:Aldosterone; D000242:Cyclic AMP; D017346:Protein Serine-Threonine Kinases; D054770:G-Protein-Coupled Receptor Kinase 3; C517848:GRK3 protein, human; D007545:Isoproterenol