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Dopamine Receptor D1R and D3R and GRK4 Interaction in Hypertension
Chunyu Zeng1, Ines Armando2, Jian Yang3
1Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), Chongqing, P. R. China.
The Yale Journal of Biology and Medicine
|April 3, 2023
Summary
Essential hypertension involves genetic and environmental factors affecting renal ion transport. Impaired dopamine receptor function, particularly D1R and D3R, due to GRK4 variants, contributes to high blood pressure.
Area of Science:
- Nephrology
- Pharmacology
- Genetics
Background:
- Essential hypertension arises from complex genetic, behavioral, and environmental interactions.
- Renal ion transport abnormalities, particularly in the dopaminergic system, are implicated in hypertension.
- The renal dopaminergic system regulates sodium excretion via G protein-coupled receptors (GPCRs), including D1-like (D1R, D5R) and D2-like (D2R, D3R, D4R) receptors.
Purpose of the Study:
- To review the roles of dopamine receptor 1 (D1R) and dopamine receptor 3 (D3R) in regulating renal sodium transport and blood pressure.
- To explore the interaction between D1R and D3R in natriuresis during volume expansion.
- To examine the mechanisms underlying D1R and D3R dysfunction in hypertension, focusing on the role of GRK4.
Main Methods:
- Review of existing literature on renal dopaminergic system, dopamine receptors (D1R, D3R), and their relation to hypertension.
- Analysis of signaling pathways (PKA, PKC) and protein degradation mechanisms (NHE3, USP) involved in dopamine receptor function.
- Examination of genetic studies involving mouse models (Drd1, Drd3 deletion) and human polymorphisms (DRD1, DRD3, GRK4).
Main Results:
- D1R and D3R mediate inhibition of renal sodium transport through various mechanisms, including PKA/PKC pathways and NHE3 degradation.
- While D1R and D3R deletions in mice cause hypertension, human polymorphisms in DRD1 and DRD3 are not consistently associated with essential hypertension.
- GRK4 isoforms (R65L, A142V, A486V) are linked to hypertension by hyper-phosphorylating and desensitizing D1R and D3R, suggesting GRK4's role in essential hypertension's polygenic nature.
Conclusions:
- Dysfunctional D1R and D3R, often due to GRK4-mediated hyper-phosphorylation, contribute significantly to essential hypertension.
- GRK4 variants are strongly associated with high blood pressure and may explain the complex inheritance patterns of essential hypertension.
- Targeting the GRK4-dopamine receptor axis presents a potential therapeutic strategy for managing hypertension.
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