PMID:25825816

Citation	Li, F, Yang, J, Jones, JE, Villar, VA, Yu, P, Armando, I, Felder, RA and Jose, PA (2015) Sorting nexin 5 and dopamine d1 receptor regulate the expression of the insulin receptor in human renal proximal tubule cells. Endocrinology 156:2211-21
Abstract	Sorting nexin 5 (SNX5) belongs to the SNX family, which is composed of a diverse group of proteins that mediate trafficking of plasma membrane proteins, receptors, and transporters. SNX5 is important in the resensitization of the dopamine D1-like receptor (D1R). D1R is uncoupled from its effector proteins in hypertension and diabetes, and treatment of diabetes restores D1R function and insulin receptor (IR) expression. We tested the hypothesis that the D1R and SNX5 regulate IR by studying the expression, distribution, dynamics, and functional consequences of their interaction in human renal proximal tubule cells (hRPTCs). D1R, SNX5, and IR were expressed and colocalized in the brush border of RPTs. Insulin promoted the colocalization of SNX5 and IR at the perinuclear area of hRPTCs. Unlike SNX5, the D1R colocalized and coimmunoprecipitated with IR, and this interaction was enhanced by insulin. To evaluate the role of SNX5 and D1R on IR signaling, we silenced via RNA interference the endogenous expression of SNX5 or the D1R gene DRD1 in hRPTCs. We observed a decrease in IR expression and abundance of phosphorylated IR substrate and phosphorylated protein kinase B, which are crucial components of the IR signal transduction pathway. Our data indicate that SNX5 and D1R are necessary for normal IR expression and activity. It is conceivable that D1R and SNX5 may interact to increase the sensitivity to insulin via a positive regulation of IR and insulin signaling.
Links	PubMed PMC4430625 Online version:10.1210/en.2014-1638
Keywords	Blotting, Western; Cell Line; Fluorescence Resonance Energy Transfer; Humans; Immunoprecipitation; Kidney Tubules, Proximal/cytology; Microscopy, Confocal; Real-Time Polymerase Chain Reaction; Receptor, Insulin/genetics; Receptor, Insulin/metabolism; Receptors, Dopamine D1/genetics; Receptors, Dopamine D1/metabolism; Sorting Nexins/genetics; Sorting Nexins/metabolism
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:DRD1	Colocalizes with	GO:0005903: brush border	ECO:0000314:		C		Figure 4A: Dopamine D1 receptor colocalizes at the brush border of human renal proximal tubule cells.	complete CACAO 12304
HUMAN:DRD1	Colocalizes with	GO:0005899: insulin receptor complex	ECO:0000314:		C		Figure 4C: Dopamine D1 receptor colocalizes with the IR in the perinuclear area in human renal proximal tubule cells at the basal state and increasingly after administration of insulin.	complete CACAO 12305
RAT:SNX5	Colocalizes with	GO:0005903: brush border	ECO:0000314:		C		Figure 1B: SNX5 colocalizes at the brush border of renal proximal tubule cells in rat kidney.	complete CACAO 12281
HUMAN:SNX5	Colocalizes with	GO:0005899: insulin receptor complex	ECO:0000314:		C		Figure 1C: In human renal proximal tubule cells, SNX5 colocalized with the IR at the basal state and increasingly after administration of insulin.	complete CACAO 12282
HUMAN:SNX5		GO:0048471: perinuclear region of cytoplasm	ECO:0000314:		C		Figure 1C: In human renal proximal tubule cells, SNX5 colocalized with the insulin receptor in the perinuclear area	complete CACAO 12283
HUMAN:SNX5		GO:0046628: positive regulation of insulin receptor signaling pathway	ECO:0000315:		P		Figure 3A: Ratio of phosphorylated to dephosphorylated IRS1, an adaptor protein which initiates downstream insulin signaling activity, was decreased in basal-state human renal proximal tubule cells with SNX5 expression knocked down. Figure 3D: After addition of insulin, phosphorylated PKB, a downstream effector of insulin signaling, was increased to a lesser extent in human renal proximal tubule cells with SNX5 expression knocked down as compared to mock control.	complete CACAO 12302
HUMAN:SNX5		GO:0045893: positive regulation of transcription, DNA-templated	ECO:0000315:		P		Figure 2D, 2E: insulin receptor mRNA expression is decreased in human renal proximal tubule cells with SNX5 expression knocked down.	complete CACAO 12303
RAT:DRD1	Colocalizes with	GO:0005903: brush border	ECO:0000314:		C		Figure 4B: Dopamine D1 receptor colocalizes at the brush border of renal proximal tubule cells in rat kidney.	complete CACAO 12306
RAT:DRD1	Colocalizes with	GO:0005899: insulin receptor complex	ECO:0000314:		C		Figure 4B: Dopamine D1 receptor colocalized with the IR at the brush border of renal proximal tubule cells in rat kidney.	complete CACAO 12307

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