Lipid rafts are required for effective renal D₁ dopamine receptor function.

ABSTRACT: Effective receptor signaling is anchored on the preferential localization of the receptor in lipid rafts, which are plasma membrane platforms replete with cholesterol and sphingolipids. We hypothesized that the dopamine D₁ receptor (D₁ R) contains structural features that allow it to reside in lipid rafts for its activity. Mutation of C347 palmitoylation site and Y218 of a newly identified Cholesterol Recognition Amino Acid Consensus motif resulted in the exclusion of D₁ R from lipid rafts, blunted cAMP response, impaired sodium transport, and increased oxidative stress in renal proximal tubule cells (RPTCs). Kidney-restricted silencing of Drd1 in C57BL/6J mice increased blood pressure (BP) that was normalized by renal tubule-restricted rescue with D₁ R-wild-type but not the mutant D₁ R 347A that lacks a palmitoylation site. Kidney-restricted disruption of lipid rafts by β-MCD jettisoned the D₁ R from the brush border, decreased sodium excretion, and increased oxidative stress and BP in C57BL/6J mice. Deletion of the PX domain of the novel D₁ R-binding partner sorting nexin 19 (SNX19) resulted in D₁ R partitioning solely to non-raft domains, while silencing of SNX19 impaired D₁ R function in RPTCs. Kidney-restricted silencing of Snx19 resulted in hypertension in C57BL/6J mice. Our results highlight the essential role of lipid rafts for effective D₁ R signaling.

SUBMITTER: Tiu AC 

PROVIDER: S-EPMC7200283 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature