Calmodulin Is Required for Vasopressin-stimulated Increase in Cyclic AMP Production in Inner Medullary Collecting Duct

Hoffert, Jason D.; Chou, Chung‐Lin; Fenton, Robert A.; Knepper, Mark A.

doi:10.1074/jbc.m500040200

Cited by 67 publications

(99 citation statements)

References 47 publications

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“…27 Moreover, it has been speculated that Ca 2ϩ mobilization 7 and signaling mechanisms involving calmodulin/AC3 are important in CD water transport of the rat and mouse. 17,18 In comparison, AC3 is not among the most abundant isoforms in the mouse inner medulla based on mRNA expression and is not regulated by variation in fluid intake in WT or AC6 Ϫ/Ϫ mice ( Figure 4; Figure S1). Furthermore, mice that lack AC3 show apparently normal urinary flow rates and urine osmolalities.…”

Section: Discussionmentioning

confidence: 99%

“…16 The same pattern was found for mRNA expression of ACs in inner medullary CD (IMCD) suspensions of rats. 17 Based on in situ hybridization studies and the relative expression of AC6 mRNA in CD principal cells of rats, as well as studies using small interfering RNA designed to knock down AC6 in primary cultured mouse IMCD, it has been proposed that this AC isoform may contribute to AVP-stimulated cAMP formation, 18,19 although studies in rat IMCD have indicated that AVP-promoted Ca 2ϩ /calmodulin-dependent cAMP accumulation involves AC3 activity. 17 In these experiments, we examined mice that lack AC6 (AC6 Ϫ/Ϫ ) to gain insights regarding the role of AC6 in the formation of cAMP, phosphorylation of AQP2 at S256 and S269, and urinary concentration in vivo.…”

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confidence: 99%

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Adenylate Cyclase 6 Determines cAMP Formation and Aquaporin-2 Phosphorylation and Trafficking in Inner Medulla

Rieg

Tang²,

Murray³

et al. 2010

Journal of the American Society of Nephrology

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Arginine vasopressin (AVP) enhances water reabsorption in the renal collecting duct by vasopressin V 2 receptor (V 2 R)-mediated activation of adenylyl cyclase (AC), cAMP-promoted phosphorylation of aquaporin-2 (AQP2), and increased abundance of AQP2 on the apical membrane. Multiple isoforms of adenylate cyclase exist, and the roles of individual AC isoforms in water homeostasis are not well understood. Here, we found that levels of AC6 mRNA, the most highly expressed AC isoform in the inner medulla, inversely correlate with fluid intake. Moreover, mice lacking AC6 had lower levels of inner medullary cAMP, reduced abundance of phosphorylated AQP2 (at both serine-256 and serine-269), and lower urine osmolality than wild-type mice. Water deprivation or administration of the V 2 R agonist dDAVP did not increase urine osmolality of AC6-deficient mice to the levels of wild-type mice. Furthermore, AC6-deficient mice lacked dDAVP-promoted inner medullary cAMP formation and phosphorylation of serine-269 and had attenuated increases in both phosphorylation of serine-256 and apical membrane AQP2 trafficking. In summary, AC6 expression determines inner medullary cAMP formation and AQP2 phosphorylation and trafficking, the absence of which causes nephrogenic diabetes insipidus. The anti-diuretic hormone arginine-vasopressin (AVP) is the primary regulator of water reabsorption in the renal collecting duct (CD) and is critically involved in the regulation of water balance and maintenance of plasma osmolality. 1 AVP acts on the CD through the G s protein-coupled vasopressin V 2 receptor (V 2 R) to stimulate adenylyl cyclase (AC) and thus the synthesis of cAMP. 2 cAMP activates protein kinase A (PKA), which phosphorylates the water channel aquaporin-2 (AQP2) in its COOH-terminal tail on serine residue 256 (S256), thereby resulting in apical plasma membrane accumulation of AQP2. [3][4][5][6] In addition, cAMP-independent activation of AQP2 has been reported, which may involve V 2 R action of phosphoinositide-specific phospholipase C. 7 Other non-PKA-targeted AQP2 phosphorylation sites include S261, S264, and S269. 8 Phosphorylation of AQP2 at S264 and S269 requires prior phosphorylation of S256. 9 Immunohistochemistry showed that pS269-AQP2 localizes exclusively in the apical plasma

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Adenylate Cyclase 6 Determines cAMP Formation and Aquaporin-2 Phosphorylation and Trafficking in Inner Medulla

Rieg

Tang²,

Murray³

et al. 2010

Journal of the American Society of Nephrology

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“…Hoffert et al (28) previously examined the renal expression of adenylate cyclases, and also found that AC3 is present in the kidney. However, the Hoffert study focused on AC3 expression in the inner medullary collecting duct (IMCD) (demonstrated by PCR and Western blot using samples enriched for IMCD), but did not comment on its expression in the cortex.…”

Section: Discussionmentioning

confidence: 99%

Functional expression of the olfactory signaling system in the kidney

Pluznick

Zou

Zhang

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

197

215

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Olfactory-like chemosensory signaling occurs outside of the olfactory epithelium. We find that major components of olfaction, including olfactory receptors (ORs), olfactory-related adenylate cyclase (AC3) and the olfactory G protein (Golf), are expressed in the kidney. AC3 and Golf colocalize in renal tubules and in macula densa (MD) cells which modulate glomerular filtration rate (GFR). GFR is significantly reduced in AC3 ؊/؊ mice, suggesting that AC3 participates in GFR regulation. Although tubuloglomerular feedback is normal in these animals, they exhibit significantly reduced plasma renin levels despite up-regulation of COX-2 expression and nNOS activity in the MD. Furthermore, at least one member of the renal repertoire of ORs is expressed in a MD cell line. Thus, key components of olfaction are expressed in the renal distal nephron and may play a sensory role in the MD to modulate both renin secretion and GFR.adenylate cyclase 3 ͉ glomerular filtration rate ͉ Golf ͉ macula densa ͉ renin

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“…6, A and B, inset). Several pieces of evidence suggest that calmodulin-sensitive adenylyl cyclase type 3 plays an important role in mediating the AVP-induced increase of intracellular cAMP (39). Accordingly, calmodulin inhibition blocked VP-induced redistribution of AQP2 toward the cell surface, at least partly by attenuating adenylyl cyclase-mediated cAMP elevation (39).…”

Section: Increased Aqp2 Expression At the Cell Surface And Transgolgimentioning

confidence: 99%

“…Several pieces of evidence suggest that calmodulin-sensitive adenylyl cyclase type 3 plays an important role in mediating the AVP-induced increase of intracellular cAMP (39). Accordingly, calmodulin inhibition blocked VP-induced redistribution of AQP2 toward the cell surface, at least partly by attenuating adenylyl cyclase-mediated cAMP elevation (39). We further investigated the influence of cAMP concentration on hypertonicity-induced altered AQP2 trafficking by treating mCCD cl1 and LLC-AQP2 cells with either of two different calmodulin inhibitors (200 M monodansylcadaverine (MDC) and 25 M W-7; EMD Biosciences, La Jolla, CA) (Fig.…”

Section: Increased Aqp2 Expression At the Cell Surface And Transgolgimentioning

confidence: 99%

Acute Hypertonicity Alters Aquaporin-2 Trafficking and Induces a MAPK-dependent Accumulation at the Plasma Membrane of Renal Epithelial Cells

Hasler

Nunes²,

Bouley³

et al. 2008

Journal of Biological Chemistry

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The unique phenotype of renal medullary cells allows them to survive and functionally adapt to changes of interstitial osmolality/tonicity. We investigated the effects of acute hypertonic challenge on AQP2 (aquaporin-2) water channel trafficking. In the absence of vasopressin, hypertonicity alone induced rapid (<10 min) plasma membrane accumulation of AQP2 in rat kidney collecting duct principal cells in situ, and in several kidney epithelial lines. Confocal microscopy revealed that AQP2 also accumulated in the trans-Golgi network (TGN) following hypertonic challenge. AQP2 mutants that mimic the Ser 256 -phosphorylated and -nonphosphorylated state accumulated at the cell surface and TGN, respectively. Hypertonicity did not induce a change in cytosolic cAMP concentration, but inhibition of either calmodulin or cAMP-dependent protein kinase A activity blunted the hypertonicity-induced increase of AQP2 cell surface expression. Hypertonicity increased p38, ERK1/2, and JNK MAPK activity. Inhibiting MAPK activity abolished hypertonicity-induced accumulation of AQP2 at the cell surface but did not affect either vasopressin-dependent AQP2 trafficking or hypertonicity-induced AQP2 accumulation in the TGN. Finally, increased AQP2 cell surface expression induced by hypertonicity largely resulted from a reduction in endocytosis but not from an increase in exocytosis. These data indicate that acute hypertonicity profoundly alters AQP2 trafficking and that hypertonicity-induced AQP2 accumulation at the cell surface depends on MAP kinase activity. This may have important implications on adaptational processes governing transcellular water flux and/or cell survival under extreme conditions of hypertonicity.Most mammalian cells are exposed to an extracellular environment that remains isotonic under normal physiological conditions, largely as a result of renal regulatory mechanisms that maintain water and electrolyte body fluid composition within a very narrow range. This process relies on the countercurrent concentration mechanism that occurs along the loop of Henle and which, in turn, depends on the generation of a NaCl and urea concentration gradient along the cortico-papillary axis. As a consequence, renal medullary cells are physiologically exposed to changing conditions of variable interstitial osmolality/tonicity that can reach up to 1200 mosmol/kg in human inner medulla and up to 4500 mosmol/kg in some remarkable rodent species that are adapted to life in arid desert conditions (1). The unique phenotype of these cells allows them to survive and function under these "hostile" conditions and to rapidly adapt to recurrent variations in their environmental tonicity that follow physiological and behavioral changes. In addition to the promotion of intracellular events that ensure cell survival, hypertonicity also promotes events that mediate changes in cell function in various physiological settings. Both rapid and slow responses mediate cell adaptation to increased extracellular tonicity. Rapid responses include actin and micr...

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Calmodulin Is Required for Vasopressin-stimulated Increase in Cyclic AMP Production in Inner Medullary Collecting Duct

Cited by 67 publications

References 47 publications

Adenylate Cyclase 6 Determines cAMP Formation and Aquaporin-2 Phosphorylation and Trafficking in Inner Medulla

Adenylate Cyclase 6 Determines cAMP Formation and Aquaporin-2 Phosphorylation and Trafficking in Inner Medulla

Functional expression of the olfactory signaling system in the kidney

Acute Hypertonicity Alters Aquaporin-2 Trafficking and Induces a MAPK-dependent Accumulation at the Plasma Membrane of Renal Epithelial Cells

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