Adenylyl cyclase types I and VI but not II and V are selectively inhibited by nitric oxide

Goldstein, Jorge; Silberstein, Claudia; Ibarra, Cristina

doi:10.1590/s0100-879x2002000200002

Cited by 14 publications

(10 citation statements)

References 33 publications

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“…Several factors or protein kinases can inhibit AC6 activity, including nitric oxide (22,32), PKA (6), receptor tyrosine kinase activation/tyrosine phosphorylation (6,17), and PKC (6). Indeed, several of these factors have been shown to inhibit AVP-stimulated cAMP accumulation in the collecting duct (9); the finding in the present study that PKC blockade increased AVP-stimulated cAMP production supports, albeit does not prove, a role for AC6.…”

Section: Discussioncontrasting

confidence: 48%

Characterization of vasopressin-responsive collecting duct adenylyl cyclases in the mouse

Strait

Stricklett

Chapman

et al. 2010

American Journal of Physiology-Renal Physiology

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tle is known about collecting duct adenylyl cyclase (AC) isoforms or regulation in the mouse. We performed RT-PCR for AC isoforms 1-9 in microdissected cortical (CCD) and outer medullary (OMCD) and acutely isolated inner medullary (IMCD) collecting duct. All collecting duct regions contained AC3, AC4, and AC6 mRNA, while CCD and OMCD, but not IMCD, also contained AC5 mRNA. Acutely isolated IMCD expressed AC3, AC4, and AC6 proteins by Western blot analysis. The mIMCD3 cell line expressed AC2, AC3, AC4, AC5, and AC6 mRNA; M-1 CCD cells expressed AC2, 3, 4, and 6, while mpkCCD cell lines contained AC3, AC4, and AC6 mRNA. AVP stimulated cAMP accumulation in acutely isolated mouse IMCD; this was reduced by chelation of extracellular calcium (EGTA) and almost completely abolished by blockade of calmodulin (W-7). Blockade of calmodulin kinase with KN-93 or endoplasmic reticulum calcium ATPase (thapsigargin) also reduced the AVP response. A similar inhibitory effect of W-7, KN-93, and thapsigargin was seen on forskolin-stimulated cAMP content in acutely isolated mouse IMCD. These three agents had the same pattern of blockade of AVP-or forskolin-stimulated AC activity in acutely isolated rat IMCD. AVP responsiveness in primary cultures of mouse IMCD was also reduced by W-7, KN-93, and thapsigargin. Small interfering RNA (siRNA) designed to knock down AC3 or AC6 in primary cultured mouse IMCD significantly reduced AVP-stimulated cAMP accumulation. Together, these data are consistent with a role of AC3 and AC6 in the activation of mouse collecting duct by AVP. calcium; cAMP ADENYLYL CYCLASES (ACs) are key regulators of arginine vasopressin (AVP) action in the collecting duct, including modulation of water and sodium reabsorption, chloride secretion, and cell proliferation (21,43,45,57). While a host of other factors have been reported to stimulate collecting duct cAMP production, including aldosterone (46), PGI 2 (56), PGE 2 [via EP 4 (35)], ␤-adrenergic agonists (58, 62), oxytocin (61), adenosine (26), angiotensin II (30), and glucagon (1, 24), relatively (compared to AVP) few studies have examined these pathways or determined their physiological significance. Inhibitors of collecting duct cAMP production have almost exclusively been studied in the context of AVP stimulation; such negative regulators of AVP-stimulated cAMP accumulation include PGE 2 [likely via EP 3 (10)], dopamine (44), ATP (29, 41), adenosine (42), endothelin-1 (ET-1) (36), and others.Despite such extensive studies on cAMP modulation of AVP action in the collecting duct, relatively little is known about which AC isoforms are involved. There are nine membranebound and one cytoplasmic AC (6). The nine membrane-bound AC isoforms are uniquely regulated by G␣ and G␤␥ G protein subunits, divalent cations, small molecules, posttranslational modification, and subcellular localization (6). There have been some studies on AC isoform expression in the collecting duct, albeit these have been almost exclusively confined to the rat. In general, investigators have fai...

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Section: Discussioncontrasting

confidence: 48%

Characterization of vasopressin-responsive collecting duct adenylyl cyclases in the mouse

Strait

Stricklett

Chapman

et al. 2010

American Journal of Physiology-Renal Physiology

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“…We observed that inhibition of adenylyl cyclase activity and PKA completely blocked the lipolytic effect of iNOS inhibition, implying that NO suppresses lipolysis by reducing cAMP and PKA activation. Interestingly, previous reports have shown that NO inhibits adenylyl cyclase activity (29,30). Thus, the NO donor sodium nitroprusside was found to decrease forskolin-induced activation of type VI adenylyl cyclase.…”

Section: Discussionmentioning

confidence: 88%

Inducible nitric oxide synthase modulates lipolysis in adipocytes

Penfornis

Marette

2005

Journal of Lipid Research

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The role of inducible nitric oxide synthase (iNOS) in the modulation of adipocyte lipolysis was investigated. Treatment of white and brown adipose cell lines and mouse adipose explants with a mixture of tumor necrosis factor-␣ , interferon-␥ , and lipopolysaccharide (LPS) doubled the lipolytic rate, and this was associated with marked induction of iNOS expression and nitric oxide (NO) production. iNOS inhibition by 1400W, aminoguanidine, or L-NIL pretreatment further increased the cytokine/LPS-mediated lipolysis by 30% ( P Ͻ 0.05) in cultured adipocytes and in adipose explants. However, this potentiating effect of iNOS inhibition was abolished in adipose explants isolated from iNOS knockout mice. Pharmacological inhibitors of adenylyl cyclase or protein kinase A reduced cytokine/LPS-induced lipolysis and also blunted the potentiating effect of iNOS inhibition on the lipolytic rate. Furthermore, addition of the antioxidants l -cystine and l -glutathione to cytokine/LPS-stimulated adipocytes mimicked the lipolytic effect of iNOS inhibition.In conclusion, inhibition of iNOS activity in adipocytes potentiates cytokine/LPS-induced lipolysis. This effect was fully reversed by adenylyl cyclase and protein kinase A inhibitors but was mimicked by cellular antioxidants. These data suggest that iNOS-mediated NO production counteracts cytokine/LPS-mediated lipolysis in adipocytes and that this feedback mechanism involves an oxidative process upstream of cAMP production in the signaling pathway. -Penfornis, P., and A. Marette. Major metabolic changes occur during sepsis as proinflammatory cytokines and endotoxins markedly affect energy metabolism in liver and peripheral tissues (reviewed in 1, 2). In vivo studies have shown that adipose tissue lipolysis is markedly increased in sepsis and other acute inflammatory settings, leading to an increased VLDL secretion and hepatic fatty acid synthesis. The lipolytic effect of cytokines and endotoxins can be reproduced in vitro using freshly isolated adipocytes or cultured adipose cell lines (3). Unlike ␤ -adrenergic agonists, which stimulate lipolysis within minutes through activation of the adenylyl cyclase/cAMP/protein kinase A (PKA) pathway, inflammatory cytokines such as tumor necrosis factor-␣ (TNF-␣ ) increase lipolysis only after long-term activation (hours) via activation of Ras-extracellular signal regulated kinase (ERK), which in turns promotes phosphorylation and activation of Hormone-sensitive lipase (HSL) and its translocation on cellular lipid droplets (3-6). TNF-␣ may also cause lipolysis through ERK-dependent inhibition of cyclic nucleotide phosphodiesterase 3B (PDE3B), increasing intracellular cAMP and PKA activity, leading to phosphorylation and decreased expression of perilipins (7-9). Perilipins are phosphoproteins located at the surface of the intracellular lipid droplets that have been proposed to act as a barrier to lipolysis (9-11).Sepsis is also associated with marked expression of inducible nitric oxide synthase (iNOS), a proinflammatory mediator i...

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“…The AC6 isoform is inhibited by nitric oxide, protein kinase A (PKA), receptor tyrosine kinases, protein kinase C, and other factors. 16,[44][45][46] AC6 is also inhibited by submicromolar Ca 2+ concentrations 47 possibly via capacitive Ca 2+ entry. 16,48 Indeed, several of these factors, including nitric oxide and protein kinase C, have been shown to inhibit AVP-stimulated cAMP accumulation in the CD.…”

Section: Discussionmentioning

confidence: 99%

Adenylyl Cyclase VI Mediates Vasopressin-Stimulated ENaC Activity

Roos

Bugaj

Mironova

et al. 2013

Journal of the American Society of Nephrology

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Vasopressin modulates sodium reabsorption in the collecting duct through adenylyl cyclase-stimulated cyclic AMP, which exists as multiple isoforms; the specific isoform involved in vasopressin-stimulated sodium transport is unknown. To assess this, we studied mice deficient in adenylyl cyclase type VI specifically in the principal cells of the collecting duct. Knockout mice had increased urine volume and reduced urine sodium concentration, but regardless of the level of sodium intake, they did not exhibit significant alterations in urinary sodium excretion, arterial pressure, or pulse rate. Plasma renin concentration was elevated in knockout mice, however, suggesting a compensatory response. Valsartan significantly reduced arterial pressure in knockout mice but not in controls. Knockout mice had decreased renal cortical mRNA content of all three epithelial sodium channel (ENaC) isoforms, and total cell sodium channel isoforms a and g were reduced in these animals. Patch-clamp analysis of split-open cortical collecting ducts revealed no difference in baseline activity of sodium channels, but knockout mice had abolished vasopressinstimulated ENaC open probability and apical membrane channel number. In summary, these data suggest that adenylyl cyclase VI mediates vasopressin-stimulated ENaC activity in the kidney. Arginine vasopressin (AVP) modulation of water flux across the renal collecting duct (CD) is well known; however, it is becoming increasingly apparent that AVP stimulation of epithelial Na channel (ENaC)-mediated Na transport is of substantial importance in Na and water homeostasis. Recent studies indicate that AVP-induced Na reabsorption is important in the hormone's stimulation of water reabsorption (reviewed in Stockand 1 ). Exogenous AVP enhances renal expression of all ENaC subunits in Brattleboro rats, 2 increases ENaC open probability (Po) in MDCK cells, 3 and stimulates Na flux in isolated perfused CD. 4 A 2-to 3-minute exposure to AVP was shown to increase ENaC Po in the split-open isolated mouse cortical CD (CCD); in addition, 30-minute exposure to AVP increased the ENaC apical membrane channel number (N). 5 Recent studies by our group showed that adrenalectomy surprisingly did not reduce renal ENaC abundance, whereas adrenalectomy and AVP V2 receptor antagonism markedly decreased renal ENaC levels. 6 The stimulatory effects of AVP on ENaC are mediated by cAMP. In the split-open mouse CCD, the AVP effect was dependent upon adenylyl cyclase (AC) activity, whereas AVPenhanced apical membrane Na conductance in perfused rat CCD was mediated by cAMP. 4 cAMP increases ENaC Po and N in pulmonary epithelial cells, transfected oocytes, CCD cell lines, cultured CDs, and MDCK cells. [7][8][9][10][11][12] The effect of cAMP on ENaC trafficking is due, at least in part, to inhibition of Nedd4-2-induced ENaC ubiquitination via phosphorylation of Nedd4-2 on Ser 327 , Ser 221 , and Thr 246 ; notably, these are the same residues that are phosphorylated by serum and glucocorticoid-inducible

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Adenylyl cyclase types I and VI but not II and V are selectively inhibited by nitric oxide

Cited by 14 publications

References 33 publications

Characterization of vasopressin-responsive collecting duct adenylyl cyclases in the mouse

Characterization of vasopressin-responsive collecting duct adenylyl cyclases in the mouse

Inducible nitric oxide synthase modulates lipolysis in adipocytes

Adenylyl Cyclase VI Mediates Vasopressin-Stimulated ENaC Activity

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