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PMID:23195037

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Citation

Villar, VA, Armando, I, Sanada, H, Frazer, LC, Russo, CM, Notario, PM, Lee, H, Comisky, L, Russell, HA, Yang, Y, Jurgens, JA, Jose, PA and Jones, JE (2013) Novel role of sorting nexin 5 in renal D(1) dopamine receptor trafficking and function: implications for hypertension. FASEB J. 27:1808-19

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.

Links

PubMed PMC3633819 Online version:10.1096/fj.12-208439

Keywords

Animals; Endocytosis/drug effects; G-Protein-Coupled Receptor Kinase 4/physiology; HEK293 Cells; Humans; Hypertension/physiopathology; Kidney/physiology; Male; Protein Transport/physiology; RNA, Small Interfering/pharmacology; Rats; Rats, Inbred SHR; Receptors, Dopamine D1/physiology; Sorting Nexins/physiology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

RAT:SNX5

located_in

GO:0005903: brush border

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

RAT:SNX5

located_in

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

RAT:DDR1

located_in

GO:0005903: brush border

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

RAT:DDR1

located_in

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

RAT:SNX5

part_of

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

RAT:SNX5

part_of

GO:0005903: brush border

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

RAT:SNX5

enables

GO:0031748: D1 dopamine receptor binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

RAT:SNX5

involved_in

GO:0035815: positive regulation of renal sodium excretion

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:SNX5

involved_in

GO:0045776: negative regulation of blood pressure

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

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