Na
            <sup>+</sup>
            pump low and high ouabain affinity α subunit isoforms are differently distributed in cells

Juhaszova, Magdalena; Blaustein, Mordecai P.

doi:10.1073/pnas.94.5.1800

Cited by 280 publications

(267 citation statements)

References 37 publications

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“…80 A specific colocalization of the ␣ 2 isoform of the Na ϩ ,K ϩ pump with the Na ϩ /Ca 2ϩ exchanger in microdomains that overlie subplasmalemmal endoplasmic reticulum was demonstrated in cultured astrocytes, suggesting a specific functional role of this isoform also in the regulation of intracellular Ca 2ϩ , particularly in the endoplasmic reticulum. 81 Indeed, elevated levels of intracellular Ca 2ϩ ions as well as elevated stores of Ca 2ϩ in the endoplasmic reticulum were measured in cultured astrocytes from Atp1a2 Ϫ/Ϫ mice. 82 In the adult somatosensory cortex the ␣ 2 Na ϩ ,K ϩ -ATPase isoform is located exclusively in glial cells and shows a localization virtually identical to that of the astrocytic glutamate transporters GLAST and GLUT1; at the ultrastructural level it appears preferentially localized in astrocytic processes around asymmetrical (glutamatergic) synaptic junctions, and not around GABAergic terminals.…”

Section: Figmentioning

confidence: 99%

Familial Hemiplegic Migraine

2007

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Summary: Familial hemiplegic migraine (FHM) is a rare and genetically heterogeneous autosomal dominant subtype of migraine with aura. Mutations in the genes CACNA1A and SCNA1A, encoding the pore-forming ␣ 1 subunits of the neuronal voltage-gated Ca 2ϩ channels Ca V 2.1 and Na ϩ channels Na V 1.1, are responsible for FHM1 and FHM3, respectively, whereas mutations in ATP1A2, encoding the ␣ 2 subunit of the Na ϩ , K ϩ adenosinetriphosphatase (ATPase), are responsible for FHM2. This review discusses the functional studies of two FHM1 knockin mice and of several FHM mutants in heterologous expression systems (12 FHM1, 8 FHM2, and 1 FHM3). These studies show the following: (1) FHM1 mutations produce gain-of-function of the Ca V 2.1 channel and, as a consequence, increased Ca V 2.1-dependent neurotransmitter release from cortical neurons and facilitation of in vivo induction and propagation of cortical spreading depression (CSD: the phenomenon underlying migraine aura); (2) FHM2 mutations produce loss-of-function of the ␣ 2 Na ϩ ,K ϩ -ATPase; and (3) the FHM3 mutation accelerates recovery from fast inactivation of Na V 1.5 (and presumably Na V 1.1) channels. These findings are consistent with the hypothesis that FHM mutations share the ability of rendering the brain more susceptible to CSD by causing either excessive synaptic glutamate release (FHM1) or decreased removal of K ϩ and glutamate from the synaptic cleft (FHM2) or excessive extracellular K ϩ (FHM3). The FHM data support a key role of CSD in migraine pathogenesis and point to cortical hyperexcitability as the basis for vulnerability to CSD and to migraine attacks. Hence, they support novel therapeutic strategies that consider CSD and cortical hyperexcitability as key targets for preventive migraine treatment.

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Section: Figmentioning

confidence: 99%

Familial Hemiplegic Migraine

2007

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“…This suggests that the low affinity ouabain binding site may correspond to the progesterone receptor on the oocyte surface. Evidence from other laboratories indicates that the low affinity and a high affinity sites are on different α1-subunits [9]. Since the low and high affinity ouabain binding α1-subunits differ by only a few amino acids, largely concentrated in the first external loop between the first and second transmembrane helices, it should be possible to identify the amino acids associated with progesterone binding.…”

Section: Introductionmentioning

confidence: 99%

Progesterone binding to the α1-subunit of the Na/K-ATPase on the cell surface: Insights from computational modeling

2008

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Progesterone triggers the resumption of meiosis in the amphibian oocyte through a signaling system at the plasma membrane. Analysis of [ 3 H]ouabain and [ 3 H]progesterone binding to the plasma membrane of the Rana pipiens oocyte indicates that progesterone competes with ouabain for a low affinity ouabain binding site on a 112 kDa α1-subunit of the membrane Na/K-ATPase. Published amino acid sequences from both low and high affinity ouabain binding α1-subunits are compared, together with published site-directed mutagenesis studies of ouabain binding. We propose that the progesterone binding site is located in the external loop (23 amino acids) between the M1-M2 transmembrane helices. Analysis of loop topology and the countercurrent hydrophobicity/polarity gradients within the M1-M2 loop further suggest that the polar β and hydrophobic α surfaces of the planar progesterone molecule interact with opposite sides of the amino acid loop. The 19-angular methyl group of progesterone is essential for activity; it could bind to the C-terminal region of the M1-M2 loop. Maximum biological activity requires formation of hydrogen-bond networks between the 3-keto group of progesterone and Arg 118 , Asp 129 and possibly Glu 122-124 in the C-terminal region of the loop. The 20-keto group hydrogen may in turn hydrogen bond to Cys 111 near the M1 helix. Peptide flexibility undergoes a maximal transition near the midway point in the M1-M2 loop, suggesting that folding occurs within the loop, which further stabilizes progesterone binding.

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“…That it is also being used in the treatment of breast cancer emphasises the importance of the ion pumps in the regulation of calcium homeostasis and cell survival. [10][11][12][13][14][15][16][17] It is not clear if different-sized CTS also bind to the same site or as strongly, and whether they block the translocation of intracellular sodium with the same potency. 2 Other Na + /K + -ATPase inhibitors include the anti-psychotic drug chlorpromazine, the anti-malarial agent chloroquine and the antibiotic gramicidine A (IC 50 = 8 μM) ( Table 1).…”

Section: Na + /K + -Atpase Inhibitorsmentioning

confidence: 99%

“…2 Other Na + /K + -ATPase inhibitors include the anti-psychotic drug chlorpromazine, the anti-malarial agent chloroquine and the antibiotic gramicidine A (IC 50 = 8 μM) ( Table 1). [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] These drugs also affect other proteins, however, and the effects on the Na + /K + -ATPase are only observed for higher concentrations. 18,19 Monomeric vanadate is a well-known Na + /K + -ATPase inhibitor which is selective towards the E2P conformation.…”

Section: Na + /K + -Atpase Inhibitorsmentioning

confidence: 99%

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Ion pumps as biological targets for decavanadate

2013

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The putative applications of poly-, oligo-and mono-oxometalates in biochemistry, biology, pharmacology and medicine are rapidly attracting interest. In particular, these compounds may act as potent ion pump inhibitors and have the potential to play a role in the treatment of e.g. ulcers, cancer and ischemic heart disease. However, the mechanism of action is not completely understood in most cases, and even remains largely unknown in other cases. In the present review we discuss the most recent insights into the interaction between mono-and polyoxometalate ions with ion pumps, with particular focus on the interaction of decavanadate with Ca 2+ -ATPase. We also compare the proposed mode of action with those of established ion pump inhibitors which are currently in therapeutic use. Of the 18 classes of compounds which are known to act as ion pump inhibitors, the complete mechanism of inhibition is only known for a handful. It has, however, been established that most ion pump inhibitors bind mainly to the E2 ion pump conformation within the membrane domain from the extracellular side and block the cation release. Polyoxometalates such as decavanadate, in contrast, interact with Ca 2+ -ATPase near the nucleotide binding site domain or at a pocket involving several cytoplasmic domains, and therefore need to cross through the membrane bilayer.In contrast to monomeric vanadate, which only binds to the E2 conformation, decavanadate binds to all protein conformations, i.e. E1, E1P, E2 and E2P. Moreover, the specific interaction of decavanadate with sarcoplasmic reticulum Ca 2+ -ATPase has been shown to be non-competitive with respect to ATP and induces protein cysteine oxidation with concomitant vanadium reduction which might explain the high inhibitory capacity of V 10 (IC 50 = 15 μM) which is quite similar to the majority of the established therapeutic drugs.

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Na ⁺ pump low and high ouabain affinity α subunit isoforms are differently distributed in cells

Cited by 280 publications

References 37 publications

Familial Hemiplegic Migraine

Familial Hemiplegic Migraine

Progesterone binding to the α1-subunit of the Na/K-ATPase on the cell surface: Insights from computational modeling

Ion pumps as biological targets for decavanadate

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Na + pump low and high ouabain affinity α subunit isoforms are differently distributed in cells

Cited by 280 publications

References 37 publications

Familial Hemiplegic Migraine

Familial Hemiplegic Migraine

Progesterone binding to the α1-subunit of the Na/K-ATPase on the cell surface: Insights from computational modeling

Ion pumps as biological targets for decavanadate

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Product

Resources

About

Na ⁺ pump low and high ouabain affinity α subunit isoforms are differently distributed in cells