Dopamine 5 receptor mediates Ang II type 1 receptor degradation via a ubiquitin-proteasome pathway in mice and human cells.
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.
Li
Hewang
H
Department of Pediatrics, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
Armando
Ines
I
Yu
Peiying
P
Escano
Crisanto
C
Mueller
Susette C
SC
Asico
Laureano
L
Pascua
Annabelle
A
Lu
Quansheng
Q
Wang
Xiaoyan
X
Villar
Van Anthony M
VA
Jones
John E
JE
Wang
Zheng
Z
Periasamy
Ammasi
A
Lau
Yuen-Sum
YS
Soares-da-Silva
Patricio
P
Creswell
Karen
K
Guillemette
Gaétan
G
Sibley
David R
DR
Eisner
Gilbert
G
Gildea
John J
JJ
Felder
Robin A
RA
Jose
Pedro A
PA
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*
C493605:DRD5 protein, human; C493606:Drd5 protein, mouse; D011945:Receptors, Angiotensin; D025801:Ubiquitin; D050641:Receptors, Dopamine D5; D046988:Proteasome Endopeptidase Complex