1. Dopamine 5 receptor mediates Ang II type 1 receptor degradation via a ubiquitin-proteasome pathway in mice and human cells
- Author
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Li, Hewang, Armando, Ines, Yu, Peiying, Escano, Crisanto, Mueller, Susette C., Asico, Laureano, Pascua, Annabelle, Lu, Quansheng, Wang, Xiaoyan, Villar, Anthony M. Van, Jones, John E., Wang, Zheng, Periasamy, Ammasi, Lau, Yuen-Sum, Soares-da-Silva, Patricio, Creswell, Karen, Guillemette, Gaetan, Sibley, David R., Eisner, Gilbert, Felder, Robin A., and Jose, Pedro A.
- Subjects
Angiotensin -- Health aspects ,Angiotensin -- Research ,Dopamine -- Health aspects ,Dopamine -- Research ,Hypertension -- Risk factors ,Hypertension -- Care and treatment ,Hypertension -- Research - 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 ([D.sub.5]R) and the prohypertensive Ang II type 1 receptor ([AT.sub.1]R). In this report, we investigated the in vivo and in vitro interaction between these GPCRs. Disruption of the gene encoding [D.sub.5]R in mice increased both blood pressure and [AT.sub.1]R protein expression, and the increase in blood pressure was reversed by [AT.sub.1]R blockade. Activation of [D.sub.5]R increased the degradation of glycosylated [AT.sub.1]R in proteasomes in HEK cells and human renal proximal tubule cells heterologously and endogenously expressing human [AT.sub.1]R and [D.sub.5]R. Confocal microscopy, Forster/fluorescence resonance energy transfer microscopy, and fluorescence lifetime imaging microscopy revealed that activation of [D.sub.5]R initiated ubiquitination of the glycosylated [AT.sub.1]R at the plasma membrane. The regulated degradation of [AT.sub.1]R via a ubiquitin/proteasome pathway by activation of [D.sub.5]R 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 [AT.sub.1]R and the [D.sub.5]R., Introduction Hypertension is associated with sodium retention caused by decreased renal sodium excretion, which is tightly regulated by both natriuretic and antinatriuretic hormones. Dopamine and Ang II are among those [...]
- Published
- 2008