Disruption of the type 2 dopamine receptor gene causes a sodium-dependent increase in blood pressure in mice

Ueda, Atsushi; Ozono, Ryoji; Oshima, Tetsuya; Yano, Ai; Kambe, Masayuki; Teranishi, Yasuhiro; Katsuki, Motoya; Chayama, Kazuaki

doi:10.1016/s0895-7061(03)01013-6

Cited by 35 publications

(37 citation statements)

References 15 publications

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“…Hypertension was found in mice with deletion of both D 1 -like receptors (D 1 and D 5 ) (1, 31) and D 2 -like receptors (D 2 , D 3 , and D 4 ) (6,11,42). A multitude of cardiovascular, neurohumoral, and renal mechanisms may contribute to the phenotypes of these mice, but both D 1 -like and D 2 -like receptor deletions have been associated with sodium retention, extracellular fluid expansion, and salt-sensitive hypertension (1,6,42,54). The importance of the intrarenal autocrine/paracrine dopamine system in the natriuretic response to both acute and chronic sodium loading has also been demonstrated by pharmacological inhibition of the aromatic amino acid decarboxylase (8,53) and blockade of the renal dopamine receptors (28,29,39,47,49).…”

Section: Discussionmentioning

confidence: 99%

Acute regulation of renal Na⁺/H⁺ exchanger NHE3 by dopamine: role of protein phosphatase 2A

Bobulescu

Quiñones²,

Gisler³

et al. 2010

American Journal of Physiology-Renal Physiology

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mine is a potent natriuretic paracrine/autocrine hormone that is central for mammalian sodium homeostasis. In the renal proximal tubule, dopamine induces natriuresis partly via inhibition of the sodium/ proton exchanger NHE3. The signal transduction pathways and mechanisms by which dopamine inhibits NHE3 are complex and incompletely understood. This manuscript describes the role of the serine/ threonine protein phosphatase 2A (PP2A) in the regulation of NHE3 by dopamine. The PP2A regulatory subunit B56␦ (coded by the Ppp2r5d gene) directly associates with more than one region of the carboxy-terminal hydrophilic putative cytoplasmic domain of NHE3 (NHE3-cyto), as demonstrated by yeast-two-hybrid, coimmunoprecipitation, blot overlay, and in vitro pull-down assays. Phosphorylated NHE3-cyto is a substrate for purified PP2A in an in vitro dephosphorylation reaction. In cultured renal cells, inhibition of PP2A by either okadaic acid or by overexpression of the simian virus 40 (SV40) small T antigen blocks the ability of dopamine to inhibit NHE3 activity and to reduce surface NHE3 protein. Dopamineinduced NHE3 redistribution is also blocked by okadaic acid ex vivo in rat kidney cortical slices. These studies demonstrate that PP2A is an integral and critical participant in the signal transduction pathway between dopamine receptor activation and NHE3 inhibition. natriuresis; sodium transport; signal transduction THE INTRARENAL AUTOCRINE/PARACRINE dopamine natriuretic system is critical for mammalian sodium homeostasis (5,8,28,29,37,39,47,49,53). The dopamine precursor 3,4-dihydroxy-Lphenylalanine (L-DOPA) is taken up from the glomerular filtrate and plasma into the proximal tubule (48, 50), decarboxylated to dopamine by the action of the cytoplasmic aromatic amino acid decarboxylase (61), and dopamine is extruded into the urinary lumen as well as the interstitial space (43,51,58). Dopamine locally controls multiple aspects of renal function including renal blood flow, glomerular filtration rate, the setting of tubuloglomerular feedback, renin release, and Na ϩ absorption by the renal tubules (5, 37). Quantitatively, the most important mechanism by which dopamine induces natriuresis is direct suppression of Na ϩ absorption by the renal tubular epithelium (9,20,27,40). Inhibition of proximal Na ϩ absorption translates into effective whole kidney natriuresis because downstream of the proximal tubule, dopamine also inhibits Na ϩ absorption in the thick ascending loop of Henle, tubuloglomerular feedback, and Na ϩ transporters in the distal nephron (37). In the proximal tubule, dopamine inhibits the two principal Na ϩ transporters: the apical membrane Na ϩ /H ϩ exchanger NHE3 (7,23,26,33,59,60) and the basolateral Na ϩ -K ϩ -ATPase (4, 12, 13). Inhibition of NHE3 by dopamine involves reduced transport activity and increased endocytosis (7,33,59) and is associated with NHE3 phosphorylation (33, 64). Two PKA phosphorylation sites (serines 552 and 605 in rat NHE3) are necessary but not sufficient for PKA-mediated NHE3 regulation ...

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Section: Discussionmentioning

confidence: 99%

Acute regulation of renal Na⁺/H⁺ exchanger NHE3 by dopamine: role of protein phosphatase 2A

Bobulescu

Quiñones²,

Gisler³

et al. 2010

American Journal of Physiology-Renal Physiology

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“…Those studies demonstrated that tyramine, octopamine, and dopamine can modulate chloride conductance in isolated Malpighian tubules. In mammals, it is well known that D2-like receptors are expressed in the kidney (Ricci et al, 2002;Nurnberger et al, 2004) where they modulate dopamine induced sodium excretion (Asico et al, 1998;Ueda et al, 2003). Taken together, these observations suggest that the fly may be utilized to investigate mechanisms underlying a range of D2 receptor-mediated physiogical processes.…”

Section: Figure 6 (Continued)mentioning

confidence: 99%

Locomotor activity is regulated by D2‐like receptors in Drosophila: An anatomic and functional analysis

Draper

Kurshan

McBride

et al. 2007

Developmental Neurobiology

111

101

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In mammals, dopamine 2-like receptors are expressed in distinct pathways within the central nervous system, as well as in peripheral tissues. Selected neuronal D2-like receptors play a critical role in modulating locomotor activity and, as such, represent an important therapeutic target (e.g. in Parkinson's disease). Previous studies have established that proteins required for dopamine (DA) neurotransmission are highly conserved between mammals and the fruit fly Drosophila melanogaster. These include a fly dopamine 2-like receptor (DD2R; Hearn et al. PNAS 2002 99(22):14554) that has structural and pharmacologic similarity to the human D2-like (D2R). In the current study, we define the spatial expression pattern of DD2R, and functionally characterize flies with reduced DD2 receptor levels. We show that DD2R is expressed in the larval and adult nervous systems, in cell groups that include the Ap-let cohort of peptidergic neurons, as well as in peripheral tissues including the gut and Malpighian tubules. To examine DD2R function in vivo, we generated RNA-interference (RNAi) flies with reduced DD2R expression. Behavioral analysis revealed that these flies show significantly decreased locomotor activity, similar to the phenotype observed in mammals with reduced D2R expression. The fly RNAi phenotype can be rescued by administration of the DD2R synthetic agonist bromocriptine, indicating specificity for the RNAi effect. These results suggest Drosophila as a useful system for future studies aimed at identifying modifiers of dopaminergic signaling/locomotor function.

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“…Depending on the genetic background [59,[79][80][81], knockout of all the dopamine-receptor gene subtypes in mice causes hypertension that can be aggravated by an increase in sodium chloride intake in D2 −/− , D3 −/− , D4 −/− , and D5 −/− mice; salt sensitivity of D1 −/− mice has not been tested.…”

Section: Genetic Evidence For the Role Of The D1 Receptor In Hypertenmentioning

confidence: 99%

Potential Dopamine-1 Receptor Stimulation in Hypertension Management

et al. 2011

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The role of dopamine receptors in blood pressure regulation is well established. Genetic ablation of both dopamine D1-like receptor subtypes (D1, D5) and D2-like receptor subtypes (D2, D3, D4) results in a hypertensive phenotype in mice. This review focuses on the dopamine D1-like receptor subtypes D1 and D5 (especially D1 receptors), as they play a major role in regulating sodium homeostasis and blood pressure. Studies mostly describing the role of renal dopamine D1-like receptors are included, as the kidneys play a pivotal role in the maintenance of sodium homeostasis and the long-term regulation of blood pressure. We also attempt to describe the interaction between D1-like receptors and other proteins, especially angiotensin II type 1 and type 2 receptors, which are involved in the maintenance of sodium homeostasis and blood pressure. Finally, we discuss a new concept of renal D1 receptor regulation in hypertension that involves oxidative stress mechanisms.

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Disruption of the type 2 dopamine receptor gene causes a sodium-dependent increase in blood pressure in mice

Abstract: These results suggest that D(2) receptors promote sodium excretion during a period of high salt intake. A defect in this mechanism may result in sodium-dependent BP elevation.

Cited by 35 publications

References 15 publications

Acute regulation of renal Na⁺/H⁺ exchanger NHE3 by dopamine: role of protein phosphatase 2A

Acute regulation of renal Na⁺/H⁺ exchanger NHE3 by dopamine: role of protein phosphatase 2A

Locomotor activity is regulated by D2‐like receptors in Drosophila: An anatomic and functional analysis

Potential Dopamine-1 Receptor Stimulation in Hypertension Management

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Disruption of the type 2 dopamine receptor gene causes a sodium-dependent increase in blood pressure in mice

Abstract: These results suggest that D(2) receptors promote sodium excretion during a period of high salt intake. A defect in this mechanism may result in sodium-dependent BP elevation.

Cited by 35 publications

References 15 publications

Acute regulation of renal Na+/H+ exchanger NHE3 by dopamine: role of protein phosphatase 2A

Acute regulation of renal Na+/H+ exchanger NHE3 by dopamine: role of protein phosphatase 2A

Locomotor activity is regulated by D2‐like receptors in Drosophila: An anatomic and functional analysis

Potential Dopamine-1 Receptor Stimulation in Hypertension Management

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Product

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Acute regulation of renal Na⁺/H⁺ exchanger NHE3 by dopamine: role of protein phosphatase 2A

Acute regulation of renal Na⁺/H⁺ exchanger NHE3 by dopamine: role of protein phosphatase 2A