title: Novel role of sorting nexin 5 in renal D(1) dopamine receptor trafficking and function: implications for hypertension.
abstract: 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 (Δ=-0.2±0.005 mEq/mg creatinine) and further elevates the systolic blood pressure (Δ=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.
authors.affiliation: Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, 20 Penn St., Ste. S003C, Baltimore, MD 21201, USA. vvillar@medicine.umaryland.edu
authors.forename: Van Anthony M
authors.initials: VA
authors.lastname: Villar
authors.forename: Ines
authors.initials: I
authors.lastname: Armando
authors.forename: Hironobu
authors.initials: H
authors.lastname: Sanada
authors.forename: Lauren C
authors.initials: LC
authors.lastname: Frazer
authors.forename: Christen M
authors.initials: CM
authors.lastname: Russo
authors.forename: Patricia M
authors.initials: PM
authors.lastname: Notario
authors.forename: Hewang
authors.initials: H
authors.lastname: Lee
authors.forename: Lauren
authors.initials: L
authors.lastname: Comisky
authors.forename: Holly Ann
authors.initials: HA
authors.lastname: Russell
authors.forename: Yu
authors.initials: Y
authors.lastname: Yang
authors.forename: Julie A
authors.initials: JA
authors.lastname: Jurgens
authors.forename: Pedro A
authors.initials: PA
authors.lastname: Jose
authors.forename: John E
authors.initials: JE
authors.lastname: Jones
mesh_terms: D000818:Animals; D004705:Endocytosis / Q000187:drug effects; D054771:G-Protein-Coupled Receptor Kinase 4 / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D006973:Hypertension / Q000503:physiopathology*; D007668:Kidney / Q000502:physiology*; D008297:Male; D021381:Protein Transport / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D017447:Receptors, Dopamine D1 / Q000502:physiology*; D058305:Sorting Nexins / Q000502:physiology*
chemical_list: D034741:RNA, Small Interfering; D017447:Receptors, Dopamine D1; C402667:SNX5 protein, human; D058305:Sorting Nexins; D054771:G-Protein-Coupled Receptor Kinase 4; C517855:GRK4 protein, human