title: Dopamine 5 receptor mediates Ang II type 1 receptor degradation via a ubiquitin-proteasome pathway in mice and human cells.
abstract: Hypertension is a multigenic disorder in which abnormal counterregulation between dopamine and Ang II plays a role. Recent studies suggest that this counterregulation results, at least in part, from regulation of the expression of both the antihypertensive dopamine 5 receptor (D5R) and the prohypertensive Ang II type 1 receptor (AT1R). In this report, we investigated the in vivo and in vitro interaction between these GPCRs. Disruption of the gene encoding D5R in mice increased both blood pressure and AT1R protein expression, and the increase in blood pressure was reversed by AT1R blockade. Activation of D5R increased the degradation of glycosylated AT1R in proteasomes in HEK cells and human renal proximal tubule cells heterologously and endogenously expressing human AT1R and D5R. Confocal microscopy, Förster/fluorescence resonance energy transfer microscopy, and fluorescence lifetime imaging microscopy revealed that activation of D5R initiated ubiquitination of the glycosylated AT1R at the plasma membrane. The regulated degradation of AT1R via a ubiquitin/proteasome pathway by activation of D5R provides what we believe to be a novel mechanism whereby blood pressure can be regulated by the interaction of 2 counterregulatory GPCRs. Our results therefore suggest that treatments for hypertension might be optimized by designing compounds that can target the AT1R and the D5R.
authors.affiliation: Department of Pediatrics, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Hewang
authors.initials: H
authors.lastname: Li
authors.forename: Ines
authors.initials: I
authors.lastname: Armando
authors.forename: Peiying
authors.initials: P
authors.lastname: Yu
authors.forename: Crisanto
authors.initials: C
authors.lastname: Escano
authors.forename: Susette C
authors.initials: SC
authors.lastname: Mueller
authors.forename: Laureano
authors.initials: L
authors.lastname: Asico
authors.forename: Annabelle
authors.initials: A
authors.lastname: Pascua
authors.forename: Quansheng
authors.initials: Q
authors.lastname: Lu
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Wang
authors.forename: Van Anthony M
authors.initials: VA
authors.lastname: Villar
authors.forename: John E
authors.initials: JE
authors.lastname: Jones
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wang
authors.forename: Ammasi
authors.initials: A
authors.lastname: Periasamy
authors.forename: Yuen-Sum
authors.initials: YS
authors.lastname: Lau
authors.forename: Patricio
authors.initials: P
authors.lastname: Soares-da-Silva
authors.forename: Karen
authors.initials: K
authors.lastname: Creswell
authors.forename: Gaétan
authors.initials: G
authors.lastname: Guillemette
authors.forename: David R
authors.initials: DR
authors.lastname: Sibley
authors.forename: Gilbert
authors.initials: G
authors.lastname: Eisner
authors.forename: John J
authors.initials: JJ
authors.lastname: Gildea
authors.forename: Robin A
authors.initials: RA
authors.lastname: Felder
authors.forename: Pedro A
authors.initials: PA
authors.lastname: Jose
mesh_terms: D000818:Animals; D001794:Blood Pressure; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D005786:Gene Expression Regulation; D006031:Glycosylation; D006801:Humans; D007684:Kidney Tubules / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011945:Receptors, Angiotensin / Q000378:metabolism*; D050641:Receptors, Dopamine D5 / Q000235:genetics / Q000502:physiology*; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: C493605:DRD5 protein, human; C493606:Drd5 protein, mouse; D011945:Receptors, Angiotensin; D025801:Ubiquitin; D050641:Receptors, Dopamine D5; D046988:Proteasome Endopeptidase Complex