Regulation of Na+/K+ ATPase Transport Velocity by RNA Editing

Colina, Claudia; Palavicini, Juan Pablo; Srikumar, Deepa; Holmgren, Miguel; Rosenthal, Joshua J. C.

doi:10.1371/journal.pbio.1000540

Cited by 33 publications

(29 citation statements)

References 47 publications

(58 reference statements)

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“…For example, two messages encoding voltage-dependent potassium channels in Doryteuthis pealeii and Doryteuthis opalescens (formerly known as Loligo pealeii and Loligo opalescens) exhibited over 30 individual recoding sites (Patton et al, 1997;Rosenthal and Bezanilla, 2002). Subsequent studies on mRNAs encoding other ion channels, ion pumps and ADARs in squid revealed as many recoding editing sites in these few messages as had been identified in the entire human transcriptome (Colina et al, 2010;Liu et al, 2001;Palavicini et al, 2009;Pinto et al, 2014;Ramaswami and Li, 2014;Ramaswami et al, 2013;Rosenthal et al, 1997). It seemed unlikely that the squid studies happened upon highly edited messages by chance.…”

Section: Cephalopod Rna Editing Breaks the Rulesmentioning

confidence: 99%

“…For example, editing sites in mRNAs encoding squid potassium channels alter kinetics, subunit tetramerization and surface expression levels (Patton et al, 1997;Rosenthal and Bezanilla, 2002). A site in a mRNA encoding a Na + /K + -ATPase α-subunit increases the rate of ion pumping using a novel mechanism (Colina et al, 2010). At negative membrane potentials like the resting potential, the Na + /K + -ATPase's ability to pump Na + ions out of the cell is inhibited by both voltage and the high extracellular Na + concentration.…”

Section: Cephalopod Rna Editing Breaks the Rulesmentioning

confidence: 99%

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The emerging role of RNA editing in plasticity

Rosenthal¹

2015

Journal of Experimental Biology

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All true metazoans modify their RNAs by converting specific adenosine residues to inosine. Because inosine binds to cytosine, it is a biological mimic for guanosine. This subtle change, termed RNA editing, can have diverse effects on various RNA-mediated cellular pathways, including RNA interference, innate immunity, retrotransposon defense and messenger RNA recoding. Because RNA editing can be regulated, it is an ideal tool for increasing genetic diversity, adaptation and environmental acclimation. This review will cover the following themes related to RNA editing: (1) how it is used to modify different cellular RNAs, (2) how frequently it is used by different organisms to recode mRNA, (3) how specific recoding events regulate protein function, (4) how it is used in adaptation and (5) emerging evidence that it can be used for acclimation. Organismal biologists with an interest in adaptation and acclimation, but with little knowledge of RNA editing, are the intended audience.

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Section: Cephalopod Rna Editing Breaks the Rulesmentioning

confidence: 99%

Section: Cephalopod Rna Editing Breaks the Rulesmentioning

confidence: 99%

The emerging role of RNA editing in plasticity

Rosenthal¹

2015

Journal of Experimental Biology

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“…As expected from a mechanism that can recode almost half of all codons, the effects of RNA editing on protein function are diverse (8). The beststudied examples come from mRNAs encoding elements of the machinery for excitability in the nervous system, where editing changes ion selectivity of ionotropic glutamate receptors, G-protein coupling of metabotropic serotonin receptors, inactivation of a voltage-dependent K + channel, and the transport rate of a Na + /K + ATPase, among other things (9)(10)(11)(12). Because of its versatility, the ability to control RNA editing could prove useful for medicine and basic research.…”

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confidence: 99%

Correction of mutations within the cystic fibrosis transmembrane conductance regulator by site-directed RNA editing

Montiel-González

Vallecillo-Viejo

Yudowski

et al. 2013

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

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189

198

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Adenosine deaminases that act on RNA are a conserved family of enzymes that catalyze a natural process of site-directed mutagenesis. Biochemically, they convert adenosine to inosine, a nucleotide that is read as guanosine during translation; thus when editing occurs in mRNAs, codons can be recoded and the changes can alter protein function. By removing the endogenous targeting domains from human adenosine deaminase that acts on RNA 2 and replacing them with an antisense RNA oligonucleotide, we have engineered a recombinant enzyme that can be directed to edit anywhere along the RNA registry. Here we demonstrate that this enzyme can efficiently and selectively edit a single adenosine. As proof of principle in vitro, we correct a premature termination codon in mRNAs encoding the cystic fibrosis transmembrane conductance regulator anion channel. In Xenopus oocytes, we show that a genetically encoded version of our editase can correct cystic fibrosis transmembrane conductance regulator mRNA, restore fulllength protein, and reestablish functional chloride currents across the plasma membrane. Finally, in a human cell line, we show that a genetically encoded version of our editase and guide RNA can correct a nonfunctional version of enhanced green fluorescent protein, which contains a premature termination codon. This technology should spearhead powerful approaches to correcting a wide variety of genetic mutations and fine-tuning protein function through targeted nucleotide deamination.

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“…Two consequences of the unequal transport stoichiometry of Na þ and K þ are that steady pumping produces an outwardly directed current (1), proportional in magnitude to the turnover rate (2), which can be monitored electrically (3)(4)(5)(6)(7)(8), and that at least one step in the transport cycle must move charge through the membrane field (9). The latter implies that, under favorable conditions, charge relaxations following voltage jumps can be used to learn details about specific steps during the transport cycle (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28).…”

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confidence: 99%

Energy landscape of the reactions governing the Na ⁺ deeply occluded state of the Na ⁺ /K ⁺ -ATPase in the giant axon of the Humboldt squid

Castillo

Giorgis

Basilio

et al. 2011

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

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The Na ∕K pump is a nearly ubiquitous membrane protein in animal cells that uses the free energy of ATP hydrolysis to alternatively export 3Na from the cell and import 2K per cycle. This exchange of ions produces a steady-state outwardly directed current, which is proportional in magnitude to the turnover rate. Under certain ionic conditions, a sudden voltage jump generates temporally distinct transient currents mediated by the Na ∕K pump that represent the kinetics of extracellular Na binding/release and Na occlusion/deocclusion transitions. For many years, these events have escaped a proper thermodynamic treatment due to the relatively small electrical signal. Here, taking the advantages offered by the large diameter of the axons from the squid Dosidicus gigas, we have been able to separate the kinetic components of the transient currents in an extended temperature range and thus characterize the energetic landscape of the pump cycle and those transitions associated with the extracellular release of the first Na from the deeply occluded state. Occlusion/deocclusion transition involves large changes in enthalpy and entropy as the ion is exposed to the external milieu for release. Binding/unbinding is substantially less costly, yet larger than predicted for the energetic cost of an ion diffusing through a permeation pathway, which suggests that ion binding/unbinding must involve amino acid sidechain rearrangements at the site.P-type ATPases | pump currents | thermodynamics D uring each normal transport cycle of the Na þ ∕K þ -ATPase pump, three Na þ are exported from the cell in exchange for two K þ imported, a process driven by hydrolysis of one molecule of ATP. By establishing the Na þ and K þ gradients across cell membranes, the Na þ ∕K þ pump enables action potentials, synaptic signaling, and most solute transport in and out of cells. Two consequences of the unequal transport stoichiometry of Na þ and K þ are that steady pumping produces an outwardly directed current (1), proportional in magnitude to the turnover rate (2), which can be monitored electrically (3)(4)(5)(6)(7)(8), and that at least one step in the transport cycle must move charge through the membrane field (9). The latter implies that, under favorable conditions, charge relaxations following voltage jumps can be used to learn details about specific steps during the transport cycle (10-28).In the absence of internal and external K þ , the nominal absence of internal ADP and presence of an ATP regenerating system, the Na þ ∕K þ pump allows exchange of 3Na þ between their binding sites in a deeply occluded conformation and the external milieu (21, 29) ( Fig. 1A; encircled by dotted lines). Under these conditions there is no steady pump current observed at any voltage. Nevertheless, sudden voltage steps produce pre-steadystate currents that can be recorded (12, 13, 16-18, 21, 23, 26).These currents allow direct measurements of the rates of partial reactions of the pump cycle. Using giant axons from the squid Loligo pealeii, we have characterized th...

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Regulation of Na+/K+ ATPase Transport Velocity by RNA Editing

Abstract: Editing of Na+/K+ ATPase mRNAs modulates the Na+/K+ pump's turnover rate by selectively targeting the release of the final sodium to the outside.

Cited by 33 publications

References 47 publications

The emerging role of RNA editing in plasticity

The emerging role of RNA editing in plasticity

Correction of mutations within the cystic fibrosis transmembrane conductance regulator by site-directed RNA editing

Energy landscape of the reactions governing the Na ⁺ deeply occluded state of the Na ⁺ /K ⁺ -ATPase in the giant axon of the Humboldt squid

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Regulation of Na+/K+ ATPase Transport Velocity by RNA Editing

Abstract: Editing of Na+/K+ ATPase mRNAs modulates the Na+/K+ pump's turnover rate by selectively targeting the release of the final sodium to the outside.

Cited by 33 publications

References 47 publications

The emerging role of RNA editing in plasticity

The emerging role of RNA editing in plasticity

Correction of mutations within the cystic fibrosis transmembrane conductance regulator by site-directed RNA editing

Energy landscape of the reactions governing the Na + deeply occluded state of the Na + /K + -ATPase in the giant axon of the Humboldt squid

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Energy landscape of the reactions governing the Na ⁺ deeply occluded state of the Na ⁺ /K ⁺ -ATPase in the giant axon of the Humboldt squid