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Novel role of sorting nexin 5 in renal D(1) dopamine receptor trafficking and function: implications for hypertension.

Authors: Villar, Van Anthony M  Armando, Ines  Sanada, Hironobu  Frazer, Lauren C  Russo, Christen M  Notario, Patricia M  Lee, Hewang  Comisky, Lauren  Russell, Holly Ann  Yang, Yu  Jurgens, Julie A  Jose, Pedro A  Jones, John E 
Citation: Villar VA, etal., FASEB J. 2013 May;27(5):1808-19. doi: 10.1096/fj.12-208439. Epub 2012 Nov 29.
Pubmed: (View Article at PubMed) PMID:23195037
DOI: Full-text: DOI:10.1096/fj.12-208439

The D1 dopamine receptor (D1R) is widely expressed in the kidney and plays a crucial role in blood pressure regulation. Although much is known about D1R desensitization, especially through G-protein-coupled receptor kinase 4 (GRK4), comparatively little is known about other aspects of D1R trafficking and the proteins involved in the process. We now report the discovery of a dynamic interaction between sorting nexin 5 (SNX5), a component of the mammalian retromer, and D1R in human renal epithelial cells. We show that internalization of agonist-activated D1R is regulated by both SNX5 and GRK4, and that SNX5 is critical to the recycling of the receptor to the plasma membrane. SNX5 depletion increases agonist-activated D1R phosphorylation (>50% at basal condition), prevents D1R internalization and cAMP response, and delays receptor recycling compared to mock siRNA-transfected controls. Moreover, renal restricted subcapsular infusion of Snx5-specific siRNA (vs. mock siRNA) decreases sodium excretion (¿=-0.2±0.005 mEq/mg creatinine) and further elevates the systolic blood pressure (¿=48±5 mm Hg) in spontaneously hypertensive rats, indicating that SNX5 depletion impairs renal D1R function. These studies demonstrate an essential role for SNX5 in regulating D1R function, which may have important diagnostic, prognostic, and therapeutic implications in the management of essential hypertension.


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RGD Object Information
RGD ID: 13508622
Created: 2018-03-05
Species: All species
Last Modified: 2018-03-05
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.