Dopamine Receptor D1R and D3R and GRK4 Interaction in Hypertension.

IF 2.5 3区 工程技术 Q2 BIOLOGY
Chunyu Zeng, Ines Armando, Jian Yang, Pedro A Jose
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引用次数: 0

Abstract

Essential hypertension is caused by the interaction of genetic, behavioral, and environmental factors. Abnormalities in the regulation of renal ion transport cause essential hypertension. The renal dopaminergic system, which inhibits sodium transport in all the nephron segments, is responsible for at least 50% of renal sodium excretion under conditions of moderate sodium excess. Dopaminergic signals are transduced by two families of receptors that belong to the G protein-coupled receptor (GPCR) superfamily. D1-like receptors (D1R and D5R) stimulate, while D2-like receptors (D2R, D3R, and D4R) inhibit adenylyl cyclases. The dopamine receptor subtypes, themselves, or by their interactions, regulate renal sodium transport and blood pressure. We review the role of the D1R and D3R and their interaction in the natriuresis associated with volume expansion. The D1R- and D3R-mediated inhibition of renal sodium transport involves PKA and PKC-dependent and -independent mechanisms. The D3R also increases the degradation of NHE3 via USP-mediated ubiquitinylation. Although deletion of Drd1 and Drd3 in mice causes hypertension, DRD1 polymorphisms are not always associated with human essential hypertension and polymorphisms in DRD3 are not associated with human essential hypertension. The impaired D1R and D3R function in hypertension is related to their hyper-phosphorylation; GRK4γ isoforms, R65L, A142V, and A486V, hyper-phosphorylate and desensitize D1R and D3R. The GRK4 locus is linked to and GRK4 variants are associated with high blood pressure in humans. Thus, GRK4, by itself, and by regulating genes related to the control of blood pressure may explain the "apparent" polygenic nature of essential hypertension.

多巴胺受体D1R和D3R与GRK4在高血压中的相互作用。
原发性高血压是由遗传、行为和环境因素共同作用引起的。肾离子转运调节异常可引起原发性高血压。肾多巴胺能系统抑制钠在所有肾单位段的转运,在钠适度过量的情况下,至少负责50%的肾钠排泄。多巴胺能信号由属于G蛋白偶联受体(GPCR)超家族的两个受体家族转导。d1样受体(D1R和D5R)刺激腺苷酸环化酶,而d2样受体(D2R、D3R和D4R)抑制腺苷酸环化酶。多巴胺受体亚型自身或通过其相互作用调节肾脏钠转运和血压。我们回顾了D1R和D3R的作用,以及它们在与体积扩张相关的尿钠中的相互作用。D1R和d3r介导的肾钠转运抑制涉及PKA和pkc依赖性和非依赖性机制。D3R还通过usp介导的泛素化增加NHE3的降解。虽然小鼠中Drd1和Drd3的缺失会导致高血压,但Drd1的多态性并不总是与人类原发性高血压相关,Drd3的多态性也与人类原发性高血压无关。高血压患者D1R和D3R功能受损与其超磷酸化有关;GRK4γ亚型R65L、A142V和A486V使D1R和D3R过度磷酸化和脱敏。GRK4基因座与人类高血压有关,并且GRK4变异与高血压有关。因此,GRK4本身以及通过调节与血压控制相关的基因可以解释原发性高血压的“明显”多基因性质。
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来源期刊
Yale Journal of Biology and Medicine
Yale Journal of Biology and Medicine Biochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology
CiteScore
5.00
自引率
0.00%
发文量
41
期刊介绍: The Yale Journal of Biology and Medicine (YJBM) is a graduate and medical student-run, peer-reviewed, open-access journal dedicated to the publication of original research articles, scientific reviews, articles on medical history, personal perspectives on medicine, policy analyses, case reports, and symposia related to biomedical matters. YJBM is published quarterly and aims to publish articles of interest to both physicians and scientists. YJBM is and has been an internationally distributed journal with a long history of landmark articles. Our contributors feature a notable list of philosophers, statesmen, scientists, and physicians, including Ernst Cassirer, Harvey Cushing, Rene Dubos, Edward Kennedy, Donald Seldin, and Jack Strominger. Our Editorial Board consists of students and faculty members from Yale School of Medicine and Yale University Graduate School of Arts & Sciences. All manuscripts submitted to YJBM are first evaluated on the basis of scientific quality, originality, appropriateness, contribution to the field, and style. Suitable manuscripts are then subject to rigorous, fair, and rapid peer review.
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