title: Differential D1 and D5 receptor regulation and degradation of the angiotensin type 1 receptor.
abstract: Renal sodium transport is increased by the angiotensin type 1 receptor (AT(1)R), which is counterregulated by dopamine via unknown mechanisms involving either the dopamine type 1 (D(1)R) or dopamine type 5 receptor (D(5)R) that belong to the D(1)-like receptor family of dopamine receptors. We hypothesize that the D(1)R and D(5)R differentially regulate AT(1)R protein expression and signaling, which may have important implications in the pathogenesis of essential hypertension. D(1)R and D(5)R share the same agonists and antagonists; therefore, the selective effects of either D(1)R or D(5)R stimulation on AT(1)R expression in human renal proximal tubule cells were determined using antisense oligonucleotides selective to either D(1)R or D(5)R. We also determined the role of receptor tyrosine kinase and the proteosome on the D(1)R/D(5)R-mediated effects on AT(1)R expression and internalization. In renal proximal tubule cells, D(5)R (not D(1)R) decreased AT(1)R expression (half-life: 0.47+/-0.18 hours) and AT(1)R-mediated extracellular signal-regulated kinase 1/2 phosphorylation (232+/-18.9 U with angiotensin II [10(-7) mol/L] versus 81+/-8.9 U with angiotensin II [10(-7) mol/L] and fenoldopam [D(1)R/D(5)R agonist; 10(-6) mol/L; P<0.05; n=6). The fenoldopam-induced decrease in AT(1)R expression was reversed by 4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo (3,4-d) pyrimidine (c-Src tyrosine-kinase inhibitor) and clasto-lactacystin beta-lactone (proteasome inhibitor), demonstrating that the fenoldopam-mediated decrease in total cell AT(1)R expression is a result of a c-Src- and proteasome-dependent process. D(5)R stimulation decreases AT(1)R expression and is c-Src and proteasome dependent. The discovery of differential regulation by D(1)R and D(5)R opens new avenues for the development of agonists selective to either receptor subtype as targeted antihypertensive agents that can decrease AT(1)R-mediated antinatriuresis.
authors.affiliation: Department of Pathology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Gildea
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Wang
authors.forename: Pedro A
authors.initials: PA
authors.lastname: Jose
authors.forename: Robin A
authors.initials: RA
authors.lastname: Felder
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000081247:CSK Tyrosine-Protein Kinase; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D018491:Dopamine Agonists / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004334:Drug Administration Schedule; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D018818:Fenoldopam / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects / Q000378:metabolism*; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000502:physiology*; D050641:Receptors, Dopamine D5 / Q000819:agonists / Q000502:physiology*; D019061:src-Family Kinases
chemical_list: D018491:Dopamine Agonists; D011518:Proto-Oncogene Proteins; D044140:Receptor, Angiotensin, Type 1; D017447:Receptors, Dopamine D1; D000804:Angiotensin II; D050641:Receptors, Dopamine D5; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D048049:Extracellular Signal-Regulated MAP Kinases; D046988:Proteasome Endopeptidase Complex; D018818:Fenoldopam