The Role of Putative Phosphorylation Sites in the Targeting and Shuttling of the Aquaporin-2 Water Channel

Balkom, Bas W. M. van; Savelkoul, Paul J.M.; Markovich, Daniel; Hofman, Erik; Nielsen, Søren; Sluijs, Peter van der; Deen, Peter M.T.

doi:10.1074/jbc.m207525200

Cited by 218 publications

(209 citation statements)

References 52 publications

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“…As in other models AQP2-S256A, an AQP2 form lacking the PKA consensus motif and which thus mimics the constitutively unphosphorylated protein, does not translocate to the plasma membrane in response to FSK ( Figure 4A). 26,27 Cell surface biotinylation experiments confirmed that increased amounts of wild-type AQP2 but not of AQP2-S256A were inserted into the plasma membrane in response to cAMP elevation ( Figure 4B). Thus, in HEK293 cells ectopically expressed AQP2 is subject to regulation as it occurs in primary IMCD cells and in vivo.…”

Section: Camp Elevation Induces a Rapid Increase In Aqp2 Protein Abunmentioning

confidence: 71%

Reciprocal Regulation of Aquaporin-2 Abundance and Degradation by Protein Kinase A and p38-MAP Kinase

Nedvetsky

Tabor

Tamma

et al. 2010

Journal of the American Society of Nephrology

106

129

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Arginine-vasopressin (AVP) modulates the water channel aquaporin-2 (AQP2) in the renal collecting duct to maintain homeostasis of body water. AVP binds to vasopressin V2 receptors (V2R), increasing cAMP, which promotes the redistribution of AQP2 from intracellular vesicles into the plasma membrane. cAMP also increases AQP2 transcription, but whether altered degradation also modulates AQP2 protein levels is not well understood. Here, elevation of cAMP increased AQP2 protein levels within 30 minutes in primary inner medullary collecting duct (IMCD) cells, in human embryonic kidney (HEK) 293 cells ectopically expressing AQP2, and in mouse kidneys. Accelerated transcription or translation did not explain this increase in AQP2 abundance. In IMCD cells, cAMP inhibited p38-mitogen-activated protein kinase (p38-MAPK) via activation of protein kinase A (PKA). Inhibition of p38-MAPK associated with decreased phosphorylation (serine 261) and polyubiquitination of AQP2, preventing proteasomal degradation. Our results demonstrate that AVP enhances AQP2 protein abundance by altering its proteasomal degradation through a PKA-and p38-MAPK-dependent pathway. Aquaporin-2 (AQP2) is the water channel mediating arginine-vasopressin (AVP)-increases in water re-absorption in renal collecting duct principal cells. 1-4 AVP binds to plasma membrane-located vasopressin V2 receptors, thereby stimulating adenylyl cyclase and elevating cAMP. cAMP activates protein kinase A (PKA), which phosphorylates AQP2 at serine 256 (S256), inducing its redistribution from intracellular vesicles into the plasma membrane. 3,4 This short-term regulation of AQP2 occurs within seconds to minutes. In the case of long-term regulation, cAMP enhances AQP2 mRNA expression, followed by a rise in the AQP2 protein level within hours. 5,6 AQP2 can be degraded in proteasomes and lysosomes. 7,8 Ubiquitination directs proteins for degradation to both compartments. Monoubiquitination (mUb) is a signal for degradation in lysosomes, whereas polyubiquitination (pUb) is mainly linked to proteasomal degradation. 9 mUb of AQP2 is induced by FSK stimulation and occurs at the apical plasma membrane. 10 In WT5 cells, a model for AQP2 regulation, increased mUb of AQP2 persists

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Section: Camp Elevation Induces a Rapid Increase In Aqp2 Protein Abunmentioning

confidence: 71%

Reciprocal Regulation of Aquaporin-2 Abundance and Degradation by Protein Kinase A and p38-MAP Kinase

Nedvetsky

Tabor

Tamma

et al. 2010

Journal of the American Society of Nephrology

106

129

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“…Alternatively, Ca 2ϩ can stimulate phosphodiesterase activity in collecting ducts consistent with the presence of calcium-calmodulin-stimulated phosphodiesterase (36). A PKC-dependent AQP2 retrieval from apical membrane of principal cells has also been observed (56). Other studies suggest that calcium/PKC-coupled signaling not only inhibits water flow but also inhibits Na ϩ absorption and K ϩ secretion in the collecting ducts (26,46,59).…”

Section: Discussionmentioning

confidence: 81%

Axial heterogeneity of vasopressin-receptor subtypes along the human and mouse collecting duct

Carmosino¹,

Brooks²,

Cai³

et al. 2007

American Journal of Physiology-Renal Physiology

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Vasopressin and vasopressin antagonists are finding expanded use in mouse models of disease and in clinical medicine. To provide further insight into the physiological role of V1a and V2 vasopressin receptors in the human and mouse kidney, intrarenal localization of the receptors mRNA was determined by in situ hybridization. V2-receptor mRNA was predominantly expressed in the medulla, whereas mRNA for V1a receptors predominated in the cortex. The segmental localization of vasopressinreceptor mRNAs was determined using simultaneous in situ hybridization and immunohistochemistry for segment-specific markers, including aquaporin-2, Dolichos biflorus agglutinin, epithelial Na channels, Tamm Horsfall glycoprotein, and thiazide-sensitive Na ϩ -Cl Ϫ cotransporter. Notably, V1a receptor expression was exclusively expressed in V-ATPase/anion exchanger-1-labeled alpha-intercalated cells of the medullary collecting duct in both mouse and human kidney. In cortical collecting ducts, V1a mRNA was more widespread and detected in both principal and intercalated cells. V2-receptor mRNA is diffusely expressed along the collecting ducts in both mouse and human kidney, with higher expression levels in the medulla. These results demonstrate heterogenous axial expression of both V1a and V2 vasopressin receptors along the human and mouse collecting duct. The restricted expression of V1a-receptor mRNA in intercalated cells suggests a role for this receptor in acid-base balance. These findings further suggest distinct regulation of renal transport function by AVP through V1a and V2 receptors in the cortex vs. the medulla. in situ hybridization; vasopressin receptors; intercalated cell ARGININE VASOPRESSIN (AVP) is the key hormone responsible for producing a concentrated urine and is secreted in high concentrations during antidiuresis. At least two different vasopressin

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“…Decreased glucosuria may be linked to decreased washout of glucose by the concomitant decreased diuresis and effects on renal glucose transporters. Decreased diuresis may be linked to reversal of diabetes-induced activation of protein kinase C by highdose thiamine and benfotiamine [6] and consequent reversal of the inhibition of water re-uptake by aquaporins in renal collecting duct cells [21,22]. In any event, STZ diabetic rats with high-dose thiamine therapy consumed less food than control STZ diabetic rats whilst maintaining similar body weights.…”

Section: Discussionmentioning

confidence: 99%

High-dose thiamine therapy counters dyslipidaemia in streptozotocin-induced diabetic rats

et al. 2004

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Aims/hypothesis. Cardiovascular disease in diabetes is linked to increased risk of atherosclerosis, increased levels of triglyceride-rich lipoproteins and enhanced hepatic lipogenesis. The hepatic hexosamine pathway has been implicated in signalling for de novo lipogenesis by the liver. In this study, we assessed if decrease of flux through the hexosamine pathway induced by high-dose thiamine therapy counters diabetic dyslipidaemia. Methods. The model of diabetes used was the streptozotocin-induced diabetic rat with maintenance insulin therapy. Normal control and diabetic rats were studied for 24 weeks with and without oral high-dose therapy (7 and 70 mg/kg) with thiamine and benfotiamine. Plasma total cholesterol, HDL cholesterol and triglycerides were determined at 6-week intervals and hepatic metabolites and transketolase activity after death of the rats at 24 weeks.Results. We found that thiamine therapy (70 mg/kg) prevented diabetes-induced increases in plasma cholesterol and triglycerides in diabetic rats but did not reverse the diabetes-induced decrease of HDL. This was achieved by prevention of thiamine depletion and decreased transketolase activity in the liver of diabetic rats. There was a concomitant decrease in hepatic UDP-N-acetylglucosamine and fatty acid synthase activity. Thiamine also normalised food intake of diabetic rats. A lower dose of thiamine (7 mg/kg) and the thiamine monophosphate prodrug benfotiamine (7 and 70 mg/kg) were ineffective. Conclusions/interpretation. High-dose thiamine therapy prevented diabetic dyslipidaemia in experimental diabetes probably by suppression of food intake and hexosamine pathway signalling but other factors may also be involved. Benfotiamine was ineffective.Keywords Cholesterol · Dyslipidaemia · Glycation · Hexosamine · Streptozotocin · Thiamine · Triglycerides Abbreviations: 1,3-bis-PG, 1,3-bisphosphoglycerate · ACC, acetyl-CoA carboxylase · CEL, N ε -(1-carboxyethyl)lysine · CML, N ε -carboxymethyl-lysine · CTEP, cholesteryl ester transfer protein · DAG, diacylglycerol · DHAP, dihydroxyacetonephosphate · F-1,6-bis-P, fructose-1,6-bis-phosphate · FAS, fatty acid synthase · FL, N ε -fructosyl-

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The Role of Putative Phosphorylation Sites in the Targeting and Shuttling of the Aquaporin-2 Water Channel

Cited by 218 publications

References 52 publications

Reciprocal Regulation of Aquaporin-2 Abundance and Degradation by Protein Kinase A and p38-MAP Kinase

Reciprocal Regulation of Aquaporin-2 Abundance and Degradation by Protein Kinase A and p38-MAP Kinase

Axial heterogeneity of vasopressin-receptor subtypes along the human and mouse collecting duct

High-dose thiamine therapy counters dyslipidaemia in streptozotocin-induced diabetic rats

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