Nongastric H,K‐ATPase: Structure and Functional Properties

Modyanov, Nikolaï N.; Pestov, Nikolay B.; Adams, Gail; Crambert, Gilles; Tillekeratne, Manoranjani; Zhao, Hao; Korneenko, Tatyana V.; Shakhparonov, M. I.; Geering, Käthi

doi:10.1111/j.1749-6632.2003.tb07158.x

Cited by 6 publications

(6 citation statements)

References 11 publications

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“…It should be noted that the ngH,K-ATPase shares approximately 65% sequence homology with the gH,K-ATPase and Na,K-ATPase, and is moderately sensitive to their inhibitors. 44, 63-65 Although the inhibitory effects of PPIs on P-type ATPases besides gH,K-ATPase are largely unknown, a recent study demonstrates that omeprazole blocked another P-type ATPase, ATP7A (Menkes protein) in human epidermal melanocytes, supporting our hypothesis. 66 Additionally, our results may explain recent findings that PPI-responsiveness in esophageal biopsies of EoE patients was strongly associated with expression of KCNJ2 (gene encoding the K + channel, Kir2.1) that is colocalizes with and counteracts H,K-ATPase activity.…”

Section: Discussionsupporting

confidence: 77%

Proton pump inhibitors decrease eotaxin-3/CCL26 expression in patients with chronic rhinosinusitis with nasal polyps: Possible role of the nongastric H,K-ATPase

Min

Ocampo

Stevens

et al. 2017

Journal of Allergy and Clinical Immunology

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Background Chronic rhinosinusitis with nasal polyps (CRSwNP) is often characterized by tissue eosinophilia that is associated with poor prognosis. Recent findings that proton pump inhibitors (PPIs) directly modulate expression of eotaxin-3, an eosinophil chemoattractant, in eosinophilic diseases suggest therapeutic potential for PPIs in CRSwNP. Objective We assessed the effect of type-2 mediators, particularly IL-13 and eotaxin-3, on tissue eosinophilia and disease severity in CRS. Further investigation focused on PPI suppression of eotaxin-3 expression in vivo and in vitro with exploration of underlying mechanisms. Methods Type-2 mediator levels in nasal tissues and secretions were measured by multiplex immunoassay. Eotaxin-3 and other chemokines expressed in IL-13-stimulated human sinonasal epithelial cells (HNECs) and BEAS-2Bs with or without PPIs was assessed by using ELISA, Western blot, real-time PCR, and intracellular pH (pHi) imaging. Results Nasal tissues and secretions from CRSwNP patients had increased IL-13, eotaxin-2 and eotaxin-3 levels, and these were positively correlated with tissue ECP and radiographic scores in CRS (P<.05). IL-13-stimulation of HNECs and BEAS-2Bs dominantly induced eotaxin-3 expression, which was significantly inhibited by PPIs (P<.05). CRS patients taking PPIs also showed lower in vivo eotaxin-3 levels compared with those without PPIs (P<.05). Using pHi imaging and by altering extracellular [K+], we found that IL-13 enhanced H+,K+-exchange, which was blocked by PPIs and the mechanistically unrelated H,K-ATPase inhibitor, SCH-28080. Furthermore, knockdown of ATP12A (gene for the non-gastric H,K-ATPase [ngH,K-ATPase]) significantly attenuated IL-13-induced eotaxin-3 expression in HNECs. PPIs also had effects on accelerating IL-13-induced eotaxin-3 mRNA decay. Conclusion Our results demonstrated that PPIs reduce IL-13-induced eotaxin-3 expression by airway epithelial cells. Furthermore, mechanistic studies suggest that the ngH,K-ATPase is necessary for IL-13-mediated epithelial responses, and its inhibitors, including PPIs, may be of therapeutic value in CRSwNP by reducing epithelial production of eotaxin-3.

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Section: Discussionsupporting

confidence: 77%

Proton pump inhibitors decrease eotaxin-3/CCL26 expression in patients with chronic rhinosinusitis with nasal polyps: Possible role of the nongastric H,K-ATPase

Min

Ocampo

Stevens

et al. 2017

Journal of Allergy and Clinical Immunology

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“…Cardiac steroid‐induced responses at the cellular and molecular levels also vary (for review see Dvela et al ., 2007). For example, human non‐gastric H + ‐ and K + ‐ATPases are inhibited by bufalin, digoxin and digitoxin but are virtually resistant to digoxigenin and ouabagenin (Modyanov et al ., 2003); digoxin and digitoxin, but not ouabain, are substrates for the P‐glycoprotein transporter (Pauli‐Magnus et al ., 2001); ouabain and bufalin differentially affected the intracellular signalling protein 14‐3‐3 in rat lens (Mcgowan et al ., 1999). Finally, we recently demonstrated that digoxin, bufalin and other cardiac steroids induce the accumulation of endocytosed membrane components and cause alterations in intracellular membrane traffic.…”

Section: Introductionmentioning

confidence: 99%

Ouabain attenuates cardiotoxicity induced by other cardiac steroids

Nesher¹,

Shpolansky²,

Viola

et al. 2010

British J Pharmacology

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Background and purpose: All cardiac steroids have a similar structure, bind to and inhibit the ubiquitous transmembrane protein Na + , K + -ATPase and increase the force of contraction of heart muscle. However, there are diverse biological responses to different cardiac steroids both at the cellular and at the molecular level. Moreover, we have recently shown that ouabain inhibits digoxin-and bufalin-induced changes in membrane traffic. The present study was designed to test the hypothesis that ouabain also has an inhibitory effect on cardiotoxicity induced by other cardiac steroids. Experimental approach: The hypothesis was tested in isolated heart muscle preparations and in an in vivo model of cardiotoxicity in guinea pigs. Key results: Ouabain at a low dose attenuated the toxicity induced by bufalin and digoxin in heart muscle preparations. In addition, ouabain at the low dose (91 ng·kg ) cardiotoxicity in anaesthetized guinea pigs, as manifested by delayed arrhythmia and terminal ventricular fibrillation, as well as a reduced heart rate. In addition, as observed with ouabain, the phosphoinositide 3-kinase inhibitor wortmannin (100 mg·kg -1 ·h -1 ) delayed the digoxin-induced arrhythmia in anaesthetized guinea pigs. Conclusions and implications:The present study demonstrates the inhibitory effect, probably through signal transduction pathways, of ouabain on digoxin-and bufalin-induced cardiotoxicity in guinea pigs. Further understanding of this phenomenon could be beneficial for increasing the therapeutic window for cardiac steroids in the treatment of chronic heart failure.

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“…Membrane preparations of these cells were used for the first time to measure the principal Atp1al1-βHK catalytic functions. A preliminary account of part of this work has been presented (30,31).…”

mentioning

confidence: 99%

Catalytic Function of Nongastric H,K-ATPase Expressed in Sf-21 Insect Cells

Adams

Tillekeratne

et al. 2001

Biochemistry

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We previously demonstrated that the alpha-subunit of human nongastric H,K-ATPase (Atp1al1) can assemble with the gastric H,K-ATPase beta-subunit (betaHK) into an active ion pump upon coexpression in Xenopus oocytes. To gain insight into enzymatic functions, we have analyzed the Atp1al1-betaHK complex using a baculovirus expression system. The efficient formation of the functional Atp1al1-betaHK complex in membranes of Sf-21 insect cells was obtained upon co-infection with recombinant baculoviruses expressing Atp1al1 and betaHK. Expression of either protein alone did not produce active ATPase. The effects of K(+), Na(+), pH, and ATP and inhibitors on ATPase activity of the recombinant Atp1al1-betaHK complex were analyzed. The Atp1al1-betaHK complex was shown to exhibit significant ATPase activity in nominally K(+)-free medium. The addition of K(+) stimulated the ATP hydrolysis up to 3-fold with K(m) approximately 116 microM K(+). The ATPase activity was moderately sensitive to ouabain and to SCH 28080 with apparent K(i) values in K(+)-free medium of approximately 64 microM and approximately 93 microM, respectively. Potassium exhibited strong antagonism toward both inhibitors. Assays of the ouabain-sensitive ATPase activity revealed inhibitory effects of Na(+) with the apparent K(i) of approximately 24 mM in the absence of added K(+) and with K(i) within the range of 60-70 mM in the presence of > or = 1 mM K(+). Thus, the human nongastric H,K-ATPase represented by the recombinant Atp1al1-betaHK complex exhibits enzymatic properties of K(+)-dependent ATPase sensitive to ouabain, SCH 28080, and Na(+). It differs from Na,K-ATPase in cation dependence and differs from gastric H,K-ATPase and Na,K-ATPase in sensitivity to inhibitors.

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Nongastric H,K‐ATPase: Structure and Functional Properties

Cited by 6 publications

References 11 publications

Proton pump inhibitors decrease eotaxin-3/CCL26 expression in patients with chronic rhinosinusitis with nasal polyps: Possible role of the nongastric H,K-ATPase

Proton pump inhibitors decrease eotaxin-3/CCL26 expression in patients with chronic rhinosinusitis with nasal polyps: Possible role of the nongastric H,K-ATPase

Ouabain attenuates cardiotoxicity induced by other cardiac steroids

Catalytic Function of Nongastric H,K-ATPase Expressed in Sf-21 Insect Cells

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