Phosphorylation of the α‐subunits of the Na+/K+‐ATPase from mammalian kidneys and Xenopus oocytes by cGMP‐dependent protein kinase results in stimulation of ATPase activity

Fotis, Heike; Tatjanenko, Liliya V.; Vasilets, Larisa A.

doi:10.1046/j.1432-1327.1999.00237.x

Cited by 38 publications

(25 citation statements)

References 33 publications

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“…Subsequently, it was demonstrated that PKG phosphorylates ␣-isoform of the NKA from various species. 28 In this study, unlike phosphorylation sites for protein kinases A and C, located in the NKA ␣-subunit C and A terminus, respectively, the site for PKG phosphorylation was found to be located in the central part of the ␣-subunit polypeptide chain. The above results 28 agree with the earlier data of Scavone et al, 25 who demonstrated that low ANP concentrations, via a cGMP-dependent mechanism, inhibit the NKA from rat renal medulla.…”

Section: Discussionmentioning

confidence: 55%

“…28 In this study, unlike phosphorylation sites for protein kinases A and C, located in the NKA ␣-subunit C and A terminus, respectively, the site for PKG phosphorylation was found to be located in the central part of the ␣-subunit polypeptide chain. The above results 28 agree with the earlier data of Scavone et al, 25 who demonstrated that low ANP concentrations, via a cGMP-dependent mechanism, inhibit the NKA from rat renal medulla. Because this cGMPdependent effect has been mimicked by a protein phosphatase inhibitor, okadaic acid, it has been concluded that NKA phosphorylation is a potential target for cGMP-dependent effects of ANP.…”

Section: Discussionmentioning

confidence: 55%

“…Activation of the guanylyl cyclase-cGMP-protein kinase G (PKG) pathway underlies both renal and vascular effects of ANP peptides. [23][24][25][26] Because cGMP has been reported to regulate activity of the NKA by modulation of its phosphorylation state, 27,28 we also hypothesized that ANP would affect MBG sensitivity of the NKA via modulation of its PKG-dependent phosphorylation. Previously, ANP has been shown to inhibit renal sodium pump, 25,29,30 and both direct and indirect evidence suggest that ANP and/or cGMP can stimulate the sodium pump in the cardiovascular system.…”

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confidence: 99%

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ANP Differentially Modulates Marinobufagenin-Induced Sodium Pump Inhibition in Kidney and Aorta

et al. 2006

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Abstract-NaCl loading and plasma volume expansion stimulate 2 natriuretic systems, vasoconstrictor, digitalis-like Na/K-ATPase inhibitors and vasorelaxant ANP peptides. Several hormones, including ANP, regulate activity of the Na/K-ATPase by modulation of its phosphorylation state. We studied effects of ANP on Na/K-ATPase phosphorylation and inhibition by an endogenous sodium pump ligand, marinobufagenin, in the aorta and renal medulla from male Sprague-Dawley rats. Marinobufagenin dose-dependently inhibited the Na/K-ATPase in renal and vascular membranes at the level of higher (nanomolar) and lower affinity (micromolar) binding sites. Marinobufagenin (1 nmol/L) inhibited Na/K-ATPase in aortic sarcolemma (18%) and in renal medulla (19%). prepro-ANP 104 to 123 (ppANP) and ␣-human ANP ([␣-hANP] both 1 nmol/L) potentiated marinobufagenin-induced Na/K-ATPase inhibition in the kidney, but reversed the effect of marinobufagenin in the aorta. Similarly, ppANP and ␣-hANP modulated the sodium pump (ouabain-sensitive 86 Rb uptake) inhibitory effects of marinobufagenin in the aorta and renal medulla. In renal medulla, ppANP and ␣-hANP induced ␣-1 Na/K-ATPase phosphorylation, whereas in aorta, both peptides dephosphorylated Na/K-ATPase. The effect of ppANP on Na/K-ATPase phosphorylation and inhibition was mimicked by a protein kinase G activator, 8-Br-PET-cGMP (10 mol/L), and prevented by a protein kinase G inhibitor, KT5823 (60 nmol/L). Our results suggest that ␣-1 Na/K-ATPase inhibition by marinobufagenin in the kidney is enhanced via Na/K-ATPase phosphorylation by ANP, whereas in the aorta, ANP exerts an opposite effect. The concurrent production of a vasorelaxant, ANP, and a vasoconstrictor, marinobufagenin, potentiate each other's natriuretic effects, but ANP peptides may offset the deleterious vasoconstrictor effect of marinobufagenin. Key Words: sodium-potassium exchanging adenosinetriphosphatase Ⅲ natriuretic hormones Ⅲ ANP Ⅲ ouabain Ⅲ marinobufagenin Ⅲ cGMP T he search for the identity of natriuretic factors that become activated under conditions of sodium retention and that promote natriuresis via inhibition of the Na/KATPase (NKA) in the renal tubules evolved from the concept of a natriuretic hormone. [1][2][3][4] According to this concept, in hypertensive patients, excessive response of natriuretic sodium pump ligands produces inhibition of the sodium pump in vascular smooth muscle sarcolemma, potentiating vasoconstriction. 3 Another group of endogenous natriuretics, members of ANP family, are sensitive to NaCl loading and exhibit natriuretic properties, but, unlike digitalis-like factors, natriuretic peptides relax vascular smooth muscle. 5,6 An endogenous bufadienolide NKA inhibitor, marinobufagenin (MBG), is stimulated after acute 7-9 and chronic 10 -12 Na loading, in contrast to endogenous ouabain, which does not exhibit sustained elevations during chronic high NaCl intake 13 but, rather, becomes elevated during sodium restriction. 14 MBG exhibits greater affinity to rodent ouabain-resistant ␣-1 isoform of t...

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Section: Discussionmentioning

confidence: 55%

Section: Discussionmentioning

confidence: 55%

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confidence: 99%

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ANP Differentially Modulates Marinobufagenin-Induced Sodium Pump Inhibition in Kidney and Aorta

et al. 2006

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“…Since NO elevates the cGMP concentration in both tissues, the NO effect on the Na + /K + -ATPase may be a cGMP-dependent effect, possibly related to activation of PKG. Phosphorylation of a PKG substrate could underlie the regulatory event, and, in fact, the α-subunit of the Na + /K + -ATPase from the mammalian kidney has itself been shown to be a substrate for PKG (Fotis et al, 1999). The present effect may thus be related to cGMP-dependent phophorylation of either the α-subunit or, alternatively, a regulatory protein component, as seen for PKC modulation of the shark rectal gland enzyme (Mahmmoud et al, 2000).…”

Section: (N=6)mentioning

confidence: 98%

Regulation of Na+/K+-ATPase activity by nitric oxide in the kidney and gill of the brown trout (Salmo trutta)

Tipsmark

Madsen

2003

Journal of Experimental Biology

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SUMMARYIn teleost fish, successful osmoregulation involves controlled ion transport mechanisms in kidney and gill epithelia. In this study, the effect of nitric oxide (NO) on Na+/K+-ATPase was investigated in vitro in these two tissues in brown trout (Salmo trutta)acclimated to freshwater. The NO donor sodium nitroprusside (SNP) inhibited in situ Na+/K+-ATPase activity, measured as ouabain-sensitive Rb+ uptake, in both samples of kidney and gill tissue and in isolated gill cells. The effect was dose-dependent in both tissues, with a maximal observed inhibition of approximately 40–50% (1 mmol l –1 SNP). The time-course of inhibition revealed a maximum effect with 10 min pre-incubation. The effect of SNP was reproduced with another NO donor, papa-nonoate (NOC-15; 200 μmol l–1), and was prevented by the NO scavenger 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide (PTIO; 1 mmol l–1). To further investigate the mechanism of the NO effect,whole-tissue Na+ and K+ levels were analysed. In kidney,SNP (1 mmol l–1) led to an increase in tissue Na+levels and a decrease in K+ levels in a 3:2 ratio. In gill tissue,no change in either ion was observed. These observations indicate that the effect on Na+/K+-ATPase is direct rather than due to a decrease in intracellular Na+, its rate-limiting substrate. SNP elevated the level of cyclic GMP (cGMP) in both kidney and gill tissue. Dibutyryl cyclic GMP (db-cGMP; 1 mmol l–1) also inhibited Na+/K+-ATPase activity in both tissues. Hence, a possible mechanism may involve the cGMP-activated kinase, even though other mechanisms cannot be excluded.

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“…Studies using cGK-deficient mice demonstrated defective cGMP-mediated inhibition of platelet aggregation (5). Several proteins have been reported to be phosphorylated in response to cGK activation either in vitro or in intact cells, including cGMP-specific phosphodiesterase (6), myosin light chain kinase (7), the inositol 1,4,5-trisphosphate receptor (8), an inositol 1,4,5-trisphosphate receptor-associated cGMP kinase substrate (9), G-substrate (10), Na ϩ /K ϩ -ATPase (11), and endothelial NO synthase (Ref. 12, for review, see Ref.…”

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confidence: 99%

Heat Shock Protein 27 Is a Substrate of cGMP-dependent Protein Kinase in Intact Human Platelets

Butt¹,

Immler

Meyer

et al. 2001

Journal of Biological Chemistry

113

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Phosphorylation of heat shock protein 27 (Hsp27) in human platelets by mitogen-activated protein kinaseactivated protein kinase (MAPKAP) 2 is associated with signaling events involved in platelet aggregation and regulation of microfilament organization. We now show that Hsp27 is also phosphorylated by cGMP-dependent protein kinase (cGK), a signaling system important for the inhibition of platelet aggregation. Stimulation of washed platelets with 8-para-chlorophenylthio-cGMP, a cGK specific activator, resulted in a time-dependent phosphorylation of Hsp27. This is supported by the ability of cGK to phosphorylate Hsp27 in vitro to an extent comparable with the cGK-mediated phosphorylation of its established substrate vasodilator-stimulated phosphoprotein. Studies with Hsp27 mutants identified threonine 143 as a yet uncharacterized phosphorylation site in Hsp27 specifically targeted by cGK. To test the hypothesis that cGK could inhibit platelet aggregation by phosphorylating Hsp27 and interfering with the MAP-KAP kinase phosphorylation of Hsp27, the known MAP-KAP kinase 2-phosphorylation sites (Ser 15 , Ser 78 , and Ser 82 ) as well as Thr 143 were replaced by negatively charged amino acids, which are considered to mimic phosphate groups, and tested in actin polymerization experiments. Mimicry at the MAPKAP kinase 2 phosphorylation sites led to mutants with a stimulating effect on actin polymerization. Mutation of the cGK-specific site Thr 143 alone had no effect on actin polymerization, but in the MAPKAP kinase 2 phosphorylation-mimicking mutant, this mutation reduced the stimulation of actin polymerization significantly. These data suggest that phosphorylation of Hsp27 and Hsp27-dependent regulation of actin microfilaments contribute to the inhibitory effects of cGK on platelet function.

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Phosphorylation of the α‐subunits of the Na⁺/K⁺‐ATPase from mammalian kidneys and Xenopus oocytes by cGMP‐dependent protein kinase results in stimulation of ATPase activity

Cited by 38 publications

References 33 publications

ANP Differentially Modulates Marinobufagenin-Induced Sodium Pump Inhibition in Kidney and Aorta

ANP Differentially Modulates Marinobufagenin-Induced Sodium Pump Inhibition in Kidney and Aorta

Regulation of Na+/K+-ATPase activity by nitric oxide in the kidney and gill of the brown trout (Salmo trutta)

Heat Shock Protein 27 Is a Substrate of cGMP-dependent Protein Kinase in Intact Human Platelets

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