ArticleFASEB journal : official publication of the Federation of American Societies for Experimental Biology2014
Dopamine D3 receptor inhibits the ubiquitin-specific peptidase 48 to promote NHE3 degradation.
Article in FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 27 citations in OpenAlex.
- G protein‑coupled receptor kinase 4 governs early kidney development via STAT3 and Nhe3a.International journal of molecular medicine · 2026Article
- Role of Renal Dopamine Receptors in the Regulation of Blood Pressure.Biomolecules · 2026Review
- Caspase 3-specific cleavage of ubiquitin-specific peptidase 48 enhances drug-induced apoptosis in AML.Cancer biology & therapy · 2025Article
- USP48 deubiquitination stabilizes SLC1A5 to inhibit retinal pigment epithelium cell inflammation, oxidative stress and ferroptosis in the progression of diabetic retinopathy.Journal of bioenergetics and biomembranes · 2024Article
- Effect of DCardiology discovery · 2023Article
- Dopamine Receptor DThe Yale journal of biology and medicine · 2023Review
- The Deubiquitinating Enzyme USP48 Interacts with the Retinal Degeneration-Associated Proteins UNC119a and ARL3.International journal of molecular sciences · 2022Article
- Renal Dopamine Receptors and Oxidative Stress: Role in Hypertension.Antioxidants & redox signaling · 2021Review
- SUMOylation of the Kv4.2 Ternary Complex Increases Surface Expression and Current Amplitude by Reducing Internalization in HEK 293 Cells.Frontiers in molecular neuroscience · 2021Article
- Ubiquitin-specific peptidase 7 (USP7) and USP10 mediate deubiquitination of human NHE3 regulating its expression and activity.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2020Article
- Sorting nexin 1 loss results in increased oxidative stress and hypertension.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2020Article
- Antihypertensive effect of etamicastat in dopamine D2 receptor-deficient mice.Hypertension research : official journal of the Japanese Society of Hypertension · 2018Article
- The deubiquitinating enzyme USP48 stabilizes TRAF2 and reduces E-cadherin-mediated adherens junctions.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2018Article
- Azilsartan Improves Salt Sensitivity by Modulating the Proximal Tubular Na+-H+ Exchanger-3 in Mice.PloS one · 2016Article
- Dopamine D3 Receptor Antagonist (GSK598809) Potentiates the Hypertensive Effects of Cocaine in Conscious, Freely-Moving Dogs.The Journal of pharmacology and experimental therapeutics · 2015Article
- Antihypertensive mechanisms of intra-renal dopamine.Current opinion in nephrology and hypertension · 2015Review
- Unique regulation of human Na+/H+ exchanger 3 (NHE3) by Nedd4-2 ligase that differs from non-primate NHE3s.The Journal of biological chemistry · 2014Article
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Authors and funding
12 authors at 3 institutions in 1 country.
Funding
Abstract
The dopamine D3 receptor (D3R) is crucial in the regulation of blood pressure and sodium balance, in that Drd3 gene ablation in mice results in hypertension and failure to excrete a dietary salt load. The mechanism responsible for the renal sodium retention in these mice is largely unknown. We now offer and describe a novel mechanism by which D3R decreases sodium transport in the long term by inhibiting the deubiquitinylating activity of ubiquitin-specific peptidase 48 (USP48), thereby promoting Na(+)-H(+) exchanger (NHE)-3 degradation. We found that stimulation with the D3R-specific agonist PD128907 (1 μM, 30 min) promoted the interaction and colocalization among D3R, NHE3, and USP48; inhibited USP48 activity (-35±6%, vs. vehicle), resulting in increased ubiquitinylated NHE3 (+140±10%); and decreased NHE3 expression (-50±9%) in human renal proximal tubule cells (hRPTCs). USP48 silencing decreased NHE3's half-life (USP48 siRNA t1/2=6.1 h vs. vehicle t1/2=12.9 h), whereas overexpression of USP48 increased NHE3 half-life (t1/2=21.8 h), indicating that USP48 protects NHE3 from degradation via deubiquitinylation. USP48 accounted for ∼30% of the total deubiquitinylating activity in these cells. Extending our studies in vivo, we found that pharmacologic blockade of D3R via the D3R-specific antagonist GR103691 (1 μg/kg/min, 4 d) in C57Bl/6J mice increased renal NHE3 expression (+310±15%, vs. vehicle), whereas an innovative kidney-restricted Usp48 silencing via siRNA (3 μg/d, 7 d) increased ubiquitinylated NHE3 (+250±30%, vs. controls), decreased total NHE3 (-23±2%), and lowered blood pressure (-24±2 mm Hg), compared with that in control mice that received either the vehicle or nonsilencing siRNA. Our data demonstrate a crucial role for the dynamic interaction between D3R and USP48 in the regulation of NHE3 expression and function.
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