Desensitization of human renal D1 dopamine receptors by G protein-coupled receptor kinase 4

Watanabe, Hidetsuna; Xu, Jing; Bengra, Chikh; José, Pedro A.; Felder, Robin A.

doi:10.1046/j.1523-1755.2002.00525.x

Cited by 83 publications

(107 citation statements)

References 44 publications

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“…Amino acid numbering is given for the human GRK family members. concurrent reduction of dopamine D1 receptor desensitization, whereas loss of GRK2 in this tissue had no effect on such desensitization [29]. Very recent studies [30] that used a short interfering RNA (siRNA) approach to decrease GRK4 activity has provided strong evidence for a specific role of GRK4 in the desensitization of GABA B receptors in cerebellar granule cells.…”

Section: Grk4mentioning

confidence: 85%

Non-visual GRKs: are we seeing the whole picture?

Willets

Challiss

Nahorski

2003

Trends in Pharmacological Sciences

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G-protein-coupled receptor kinases (GRKs) comprise a family of seven mammalian serine/threonine protein kinases that phosphorylate and regulate agonist-occupied or constitutively active G-protein-coupled receptors (GPCRs). Studies of the details and consequences of these mechanisms have focused heavily on the original b-adrenoceptor kinase (b-ARK) family (GRK2 and GRK3) and, in particular, on phosphorylation-dependent recruitment of adaptor proteins such as the b-arrestins. However, recent work has indicated roles for the other, non-visual GRKs (GRK4, GRK5 and GRK6) and has revealed potential phosphorylation-independent regulation of GPCRs by GRK2 and GRK3. In this article, we review this newer information and attempt to put it into context with GRKs as physiological regulators that could be appropriate targets for future pharmacological intervention.G-protein-coupled receptors (GPCRs) constitute a very large family of heptahelical, integral membrane proteins that mediate a wide variety of physiological processes ranging from the transmission of light and odorant signals to the mediation of neurotransmission and hormonal actions [1,2]. GPCRs represent a major target for therapeutic agents, and the continuing identification of orphan GPCRs offers opportunity for future pharmacological and therapeutic development [3].Most GPCRs display a rapid loss of responsiveness in the continuing (or recurring) presence of an agonist or stimulus, and there is now substantial evidence that this process of desensitization, at least in part, is a consequence of ligand-induced phosphorylation of serine and threonine residues located within the C-terminal domain and/or the third intracellular loop of GPCRs. Two families of protein kinases appear to be predominantly involved: the G-protein-coupled receptor kinases (GRKs), which phosphorylate agonist-occupied GPCRs to mediate homologous receptor phosphorylation, and the second messengeractivated kinases, such as cAMP-dependent kinase (PKA) and protein kinase C (PKC), which can phosphorylate both ligand-bound and other inactive GPCRs in a heterologous manner [4,5]. Phosphorylation by GRKs enhances receptor affinity for non-visual b-arrestins 1 and 2 (arrestin2 and arrestin3), which not only sterically suppresses further interaction between the receptor and G proteins, but also initiates clathrin-mediated endocytosis of phosphorylated receptors and can promote the activation of additional signalling pathways by acting as agonist-regulated adaptor scaffolds [6].Other protein kinases have also been implicated in GPCR regulation. For example, evidence has accumulated that casein kinase 1a might bring about agonistmediated phosphorylation of acetylcholine muscarinic M 3 receptors and light-activated rhodopsin [7]. Casein kinase 1a-mediated phosphorylation does not appear to be associated with reduced responsiveness of the M 3 receptor but probably contributes to the activation of extracellular signal-regulated kinases 1 and 2 (ERK1,2) by this receptor [8,9].Although research in this area h...

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Section: Grk4mentioning

confidence: 85%

Non-visual GRKs: are we seeing the whole picture?

Willets

Challiss

Nahorski

2003

Trends in Pharmacological Sciences

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“…8,43 We have reported that G protein-coupled receptor kinases (GRKs), GRK2 and GRK4, are involved in D 1 receptor phosphorylation. 44 Among the GRKs, GRK2 is most impor- tant in promoting AT 1 receptor phosphorylation. 45 It is possible that the GRK2 activation subsequent to AT 1 receptor stimulation also results in the alteration of the phosphorylation and membrane localization of the D 1 receptor.…”

Section: Discussionmentioning

confidence: 99%

“…This does not occur in SHRs because the D 1 receptor is already hyperphosphorylated and fewer D 1 receptors are found on renal cell surface membranes in SHR. 46 Although GRK4 is the major GRK regulating D 1 receptor function, 43,44 GRK4 is not involved in the desensitization of the AT 1 receptor. 47 The possibility exists that the AT 1 receptor can cause heterologous desensitization of the D 1 receptor via stimulation of effector enzymes, but it is not clear which one.…”

Section: Discussionmentioning

confidence: 99%

“…8, 43 We have reported that G protein-coupled receptor kinases (GRKs), GRK2 and GRK4, are involved in D 1 receptor phosphorylation. 44 Among the GRKs, GRK2 is most impor- Long-term stimulation of AT 1 receptors increases total cellular D 1 receptor expression in WKY. This finding in vitro was also found in vivo; chronic angiotensin II infusion in mice also caused an increase in D 1 receptor expression (unpublished data).…”

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confidence: 99%

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Rat Strain Effects of AT ₁ Receptor Activation on D ₁ Dopamine Receptors in Immortalized Renal Proximal Tubule Cells

et al. 2005

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Abstract-The dopaminergic and renin-angiotensin systems regulate blood pressure, in part, by affecting sodium transport in renal proximal tubules (RPTs). We have reported that activation of a D 1 -like receptor decreases AT 1 receptor expression in the mouse kidney and in immortalized RPT cells from Wistar-Kyoto (WKY) rats. The current studies were designed to test the hypothesis that activation of the AT 1 receptor can also regulate the D 1 receptor in RPT cells, and this regulation is aberrant in spontaneously hypertensive rats (SHRs Key Words: dopamine Ⅲ kidney Ⅲ receptors, angiotensin II Ⅲ rats, spontaneously hypertensive A ngiotensin II and dopamine are important regulators of sodium and water transport across the renal proximal tubule (RPT). [1][2][3][4][5][6][7][8] Angiotensin II receptor subtypes (AT 1 , AT 2 , and AT 4 ) are expressed in brush border and basolateral membranes of RPTs. [1][2][3][4][5] The activation of AT 1 receptors by low concentrations of angiotensin II (picomolar) causes an increase in sodium reabsorption in RPTs. 1,3,6 All the dopamine receptor subtypes, D 1 -like (D 1 and D 5 ) and D 2 -like (D 2 , D 3 , and D 4 ) are also expressed in brush border and basolateral membranes of RPTs. [7][8][9][10] In contrast to the stimulatory effect of AT 1 receptors on renal sodium transport, activation of D 1 and D 3 receptors decreases renal sodium reabsorption. 7,8,[11][12][13] Several reports have shown an interaction between the dopamine and renin-angiotensin system. Intrarenally produced angiotensin II opposes the natriuretic action of the D1-like dopamine receptor agonist, fenoldopam, in rats. 14 D 2 -like receptor agonists also antagonize the stimulatory effect of angiotensin II, acting via AT 1 receptors, on renal proximal tubular luminal sodium transport. 15,16 When angiotensin II generation is inhibited or AT 1 receptors are blocked, the natriuretic effect of dopaminergic drugs is enhanced. 17 The AT 1 receptor mediates the anti-natriuretic effect of angiotensin II, whereas the D 1 dopamine receptor is responsible for Ϸ80% of D 1 -like receptor activity in RPTs. 18 We have reported that in RPT cells of Wistar-Kyoto (WKY) Methods Cell CultureImmortalized RPT cells from 4-to 8-week-old WKY and SHRs were cultured at 37°C in 95% air/5% CO 2 atmosphere in DMEM/F-12 culture media, as previously described. [21][22][23][24][25][26] The cells (80% confluence) were extracted in ice-cold lysis buffer (phosphate-buffered saline with 1% NP40, 0.5% sodium deoxycholate, 0.1% SDS, 1 mmol/L EDTA, 1 mmol/L EGTA, 1 mmol/L PMSF, 10 g/mL aprotinin, and 10 g/mL leupeptin), sonicated, kept on ice for 1 hour, and centrifuged at 16 000g for 30 minutes. The supernatants were stored at Ϫ70°C until use for immunoblotting and/or immunoprecipitation. ImmunoblottingThe antibodies are polyclonal purified antipeptides. The amino acid sequence for the immunogenic peptide (rabbit anti-human AT 1 receptor antibody) is QDDCPKAGRHC, amino acids 15 to 24 of the AT 1 receptor. The specificity of this antibody to the AT 1 ...

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“…Like many other GPCRs, the loss of responsiveness of D1R following agonist treatment reportedly involves their phosphorylation by a variety of protein kinases, including G protein-coupled receptor kinases (GRKs) (41). A recent study by Yu et al (47) has shown that renal D1R are hyperphosphorylated and uncoupled from G proteins under basal state as well.…”

mentioning

confidence: 99%

Oxidative stress reduces renal dopamine D1 receptor-G_q/11α G protein-phospholipase C signaling involving G protein-coupled receptor kinase 2

Banday¹,

Lokhandwala²

2007

American Journal of Physiology-Renal Physiology

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The dopamine D1 receptors (D1R), expressed in renal proximal tubules, participate in the regulation of sodium transport. A defect in the coupling of the D1R to its G protein/effector complex in renal tubules has been reported in various conditions associated with oxidative stress. Because G protein-coupled receptor kinases (GRKs) are known to play an important role in D1R desensitization, we tested the hypothesis that increased oxidative stress in obese Zucker rats may cause GRK2 upregulation and, subsequently, D1R dysfunction. Lean and obese rats were given normal diet or diet supplemented with antioxidant lipoic acid for 2 wk. Compared with lean rats, obese rats exhibited oxidative stress, D1R were uncoupled from G q/11␣ at basal level, and SKF-38393 failed to elicit D1R-G protein coupling, stimulate phospholipase C (PLC), and inhibit Na-K-ATPase activity. These animals showed increased basal protein kinase C (PKC) activity and membranous translocation of GRK2 and increased GKR2-G q/11␣ interaction and D1R serine phosphorylation. Enzymatic dephosphorylation of D1R restored SKF-38393-induced adenylyl cyclase stimulation but not PLC activation. Treatment of obese rats with lipoic acid restored D1R-G protein coupling and SKF-38393-induced PLC stimulation and Na-K-ATPase inhibition. Lipoic acid treatment also normalized PKC activity, GRK2 sequestration, and GKR2-G q/11␣ interaction. In conclusion, these data show that oxidative stress increases PKC activity causing GRK2 membranous translocation. GRK2 interacts with G q/11␣ and acts, at least in part, as a regulator of G protein signaling leading to the D1R-G q/11␣ uncoupling, causing inability of SKF-38393 to stimulate PLC and inhibit Na/K-ATPase. Lipoic acid, while reducing oxidative stress, normalized PKC activity and restored D1R-G q/11␣-PLC signaling and the ability of SKF-38393 to inhibit Na-K-ATPase activity. adenylyl cyclase; G proteins; sodium/potassium-adenosine 5Ј-triphosphatase; phospholipase C DOPAMINE PRODUCED IN THE KIDNEY, mainly within the proximal tubules, serves as an important regulator of renal sodium transport (reviewed in Refs. 2,18,20). There are two subtypes of dopamine receptors belonging to the superfamily of G protein-coupled receptors (GPCRs) that mediate the actions of dopamine: the D 1 -like receptors (D1 and D5) stimulate and the D 2 -like receptors (D2, D3, and D4) inhibit adenylyl cyclase (AC) activity (2,18,20). Dopamine via activation of D1 receptors (D1R) produces an increase in sodium excretion by inhibiting the activities of sodium transporters in renal proximal tubules (2,18,20). D1R activation inhibits Na/H exchanger (NHE) activity in renal brush border membranes, probably via accumulation of cAMP and subsequent activation of cAMP-dependent protein kinase (2,18,20). On the other hand, numerous studies have shown that dopamine can inhibit Na-K-ATPase activity by activating G protein-linked pathways independently of cAMP-dependent protein kinase while involving protein kinase C (PKC) (2,18,20,34).Several studies have shown tha...

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Desensitization of human renal D1 dopamine receptors by G protein-coupled receptor kinase 4

Abstract: These studies document the critical role of GRK4, relative to GRK2, in the homologous desensitization of D1 receptors in renal proximal tubule cells. However, the early phase of homologous desensitization is regulated by a non-GRK-mediated pathway.

Cited by 83 publications

References 44 publications

Non-visual GRKs: are we seeing the whole picture?

Non-visual GRKs: are we seeing the whole picture?

Rat Strain Effects of AT ₁ Receptor Activation on D ₁ Dopamine Receptors in Immortalized Renal Proximal Tubule Cells

Oxidative stress reduces renal dopamine D1 receptor-G_q/11α G protein-phospholipase C signaling involving G protein-coupled receptor kinase 2

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Desensitization of human renal D1 dopamine receptors by G protein-coupled receptor kinase 4

Abstract: These studies document the critical role of GRK4, relative to GRK2, in the homologous desensitization of D1 receptors in renal proximal tubule cells. However, the early phase of homologous desensitization is regulated by a non-GRK-mediated pathway.

Cited by 83 publications

References 44 publications

Non-visual GRKs: are we seeing the whole picture?

Non-visual GRKs: are we seeing the whole picture?

Rat Strain Effects of AT 1 Receptor Activation on D 1 Dopamine Receptors in Immortalized Renal Proximal Tubule Cells

Oxidative stress reduces renal dopamine D1 receptor-Gq/11α G protein-phospholipase C signaling involving G protein-coupled receptor kinase 2

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Rat Strain Effects of AT ₁ Receptor Activation on D ₁ Dopamine Receptors in Immortalized Renal Proximal Tubule Cells

Oxidative stress reduces renal dopamine D1 receptor-G_q/11α G protein-phospholipase C signaling involving G protein-coupled receptor kinase 2