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

Abstract

The D 1 dopamine receptor (D 1 R) is widely expressed in the kidney and plays a crucial role in blood pressure regulation. Although much is known about D 1 R desensitization, especially through G‐protein‐coupled receptor kinase 4 (GRK4), comparatively little is known about other aspects of D 1 R 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 D 1 R in human renal epithelial cells. We show that internalization of agonist‐activated D 1 R 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 D 1 R phosphorylation (>50% at basal condition), prevents D 1 R 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 D 1 R function. These studies demonstrate an essential role for SNX5 in regulating D 1 R function, which may have important diagnostic, prognostic, and therapeutic implications in the management of essential hypertension.—Villar, V. A. M., Armando, I., Sanada, H., Frazer, L. C., Russo, C. M., Notario, P. M., Lee, H., Comisky, L., Russell, H. A., Yang, Y., Jurgens, J. A., Jose, P. A., Jones, J. E. Novel role of sorting nexin 5 in renal D 1 dopamine receptor trafficking and function: implications for hypertension. FASEB J. 27, 1808–1819 (2013). www.fasebj.org