Expression and Functional Role of the γ Subunit of the Na,K-ATPase in Mammalian Cells

Therien, Alex G.; Karlish, Steven J. D.; Blostein, Rhoda

doi:10.1074/jbc.274.18.12252

Cited by 125 publications

(134 citation statements)

References 24 publications

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“…Thus, association of FXYD1 proteins with the Na,K-ATPase leads in both cases to a decreased Na ϩ affinity and inhibition of enzyme activity, whereas dissociation of the FXYD1 proteins results in stimulation of hydrolytic activity. Other FXYD proteins have different patterns of effects: association of ␥ (FXYD2) with Na,K-ATPase has been shown to increase the apparent ATP affinity by supporting the E 1 conformation of the enzyme and to decrease the apparent affinity for cytoplasmic Na ϩ , which apparently is an effect secondary to an increased antagonism of cytoplasmic K ϩ to activation by Na ϩ (10,11). In other investigations the change in apparent affinity for Na ϩ could not be unambiguously assigned to such increased Na ϩ /K ϩ competition alone but also indicated ␥ induced changes in the intrinsic binding affinity for Na ϩ (59).…”

Section: Discussionmentioning

confidence: 99%

Regulation of Na,K-ATPase by PLMS, the Phospholemman-like Protein from Shark

Mahmmoud

Cramb

Maunsbach

et al. 2003

Journal of Biological Chemistry

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In Na,K-ATPase membrane preparations from shark rectal glands, we have previously identified an FXYD domain-containing protein, phospholemman-like protein from shark, PLMS. This protein was shown to associate and modulate shark Na,K-ATPase activity in vitro. Here we describe the complete coding sequence, expression, and cellular localization of PLMS in the rectal gland of the shark Squalus acanthias. The mature protein contained 74 amino acids, including the N-terminal FXYD motif and a C-terminal protein kinase multisite phosphorylation motif. The sequence is preceded by a 20 amino acid candidate cleavable signal sequence. Immunogold labeling of the Na,K-ATPase ␣-subunit and PLMS showed the presence of ␣ and PLMS in the basolateral membranes of the rectal gland cells and suggested their partial colocalization. Furthermore, through controlled proteolysis, the C terminus of PLMS containing the protein kinase phosphorylation domain can be specifically cleaved. Removal of this domain resulted in stimulation of maximal Na,K-ATPase activity, as well as several partial reactions. Both the E 1 ϳP 3 E 2 -P reaction, which is partially rate-limiting in shark, and the K ؉ deocclusion reaction, E 2 (K) 3 E 1 , are accelerated. The latter may explain the finding that the apparent Na ؉ affinity was increased by the specific C-terminal PLMS truncation. Thus, these data are consistent with a model where interaction of the phosphorylation domain of PLMS with the Na,K-ATPase ␣-subunit is important for the modulation of shark Na,K-ATPase activity.

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Section: Discussionmentioning

confidence: 99%

Regulation of Na,K-ATPase by PLMS, the Phospholemman-like Protein from Shark

Mahmmoud

Cramb

Maunsbach

et al. 2003

Journal of Biological Chemistry

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“…As an ancillary subunit it is likely to play a modulatory role. It has been reported to increase ATP affinity when expressed in mammalian cells (18,19) and to affect the voltage sensitivity of K ϩ activation when expressed in oocytes (20). Here evidence is presented for its role in the control of the most basic property of Na,K-ATPase, the affinity for Na ϩ and K ϩ .…”

mentioning

confidence: 99%

The γ Subunit Modulates Na+ and K+Affinity of the Renal Na,K-ATPase

Arystarkhova

Wetzel

Asinovski

et al. 1999

Journal of Biological Chemistry

184

186

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The Na؉ ,K ؉ -ATPase catalyzes the active transport of ions. It has two necessary subunits, ␣ and ␤, but in kidney it is also associated with a 7.4-kDa protein, the ␥ subunit. Stable transfection was used to determine the effect of ␥ on Na,K-ATPase properties. When isolated from either kidney or transfected cells, ␣␤␥ had lower affinities for both Na ؉ and K ؉ than ␣␤. A post-translational modification of ␥ selectively eliminated the effect on Na ؉ affinity, suggesting three configurations (␣␤, ␣␤␥, and ␣␤␥*) conferring different stable properties to Na,K-ATPase. In the nephron, segment-specific differences in Na ؉ affinity have been reported that cannot be explained by the known ␣ and ␤ subunit isoforms of Na,K-ATPase. Immunofluorescence was used to detect ␥ in rat renal cortex. Cortical ascending limb and some cortical collecting tubules lacked ␥, correlating with higher Na ؉ affinities in those segments reported in the literature. Selective expression in different segments of the nephron is consistent with a modulatory role for the ␥ subunit in renal physiology.

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“…The function of the ␥ subunit is quite complex. There is evidence that it raises the affinity for ATP (13) by stabilizing the E 1 conformation of the Na-K-ATPase (12,13), and also that it reduces the enzyme's affinity for Na ϩ at cytoplasmic sites (14) by increasing the affinity of cytoplasmic K ϩ as a competitor for cytoplasmic Na ϩ (15). The ␥ subunit also affects the affinity for extracellualr K ϩ ions in a voltage-sensitive fashion and can induce nonselective cation channel activity (16).…”

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confidence: 99%

The expression of the γ subunit of Na-K-ATPase is regulated by osmolality via C-terminal Jun kinase and phosphatidylinositol 3-kinase-dependent mechanisms

Capasso

Rivard

Berl

2001

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

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The ␣ and ␤ subunits of Na-K-ATPase are up-regulated by hypertonicity in inner-medullary collecting duct cells adapted to survive in hypertonic conditions. We examined the regulation of the ␥ subunit by hypertonicity. Although cultured inner-medullary collecting duct cells lacked the ␥ subunits, both variants ␥a and ␥b were expressed in cells adapted to 600 and 900 mosmol͞KgH2O. This expression was reversible with a half-time of 17.2 ؎ 0.5 h. The message of the ␥ subunit was absent in isotonic conditions and increased with higher tonicity in adapted cells. In acute experiments the appearance of the ␥ subunit was found to be both time-dependent (>24 h) and osmolality-dependent (>500 mosmol͞KgH2O). No induction was noted with urea and only minimal induction with mannitol. Increasing concentrations of the phosphatidylinositol 3-kinase inhibitor LY294002 resulted in a dose-dependent decrement in the expression of the ␥ subunit with total abolition at 10 M. This was associated with a decrease in cell viability as <20% survived the treatment with 10 M of LY294002. Neither inhibition of extracellular response kinase nor p38 mitogen-activated protein kinase inhibited osmotic induction of the ␥ subunit. In contrast, cells transfected with a dominant negative c-Jun N-terminal kinase 2-APF construct displayed complete inhibition of the ␥ subunit. Such cells have accelerated loss of viability in hypertonic conditions. This study describes the regulation of the ␥ subunit of Na-K-ATPase by hypertonicity. This regulation is transcriptionally regulated and involves signaling mediated by phosphatidylinositol 3-kinase and c-Jun N-terminal kinase 2 pathways.

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Expression and Functional Role of the γ Subunit of the Na,K-ATPase in Mammalian Cells

Cited by 125 publications

References 24 publications

Regulation of Na,K-ATPase by PLMS, the Phospholemman-like Protein from Shark

Regulation of Na,K-ATPase by PLMS, the Phospholemman-like Protein from Shark

The γ Subunit Modulates Na+ and K+Affinity of the Renal Na,K-ATPase

The expression of the γ subunit of Na-K-ATPase is regulated by osmolality via C-terminal Jun kinase and phosphatidylinositol 3-kinase-dependent mechanisms

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