Regulation of Na+‐K+‐2Cl− cotransport in turkey red cells: the role of oxygen tension and protein phosphorylation

Muzyamba, Morris; Cossins, Andrew R.; Gibson, JS

doi:10.1111/j.1469-7793.1999.0421t.x

Cited by 52 publications

(50 citation statements)

References 42 publications

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“…Elucidation of the specific mechanisms responsible for hypoxia stimulation of the BBB cotransporter awaits further study. However, this phenomenon has also been observed in both turkey and ferret erythrocytes, where hypoxia is a major stimulus for Na-K-Cl cotransporter activity (Flatman, 2001;Muzyamba et al, 1999). The mechanism appears to involve changes in activity of an unidentified kinase in the cells, resulting in changes in phosphorylation and thus activity of the cotransporter protein (Flatman, 2002).…”

Section: Discussionmentioning

confidence: 99%

Bumetanide Inhibition of the Blood-Brain Barrier Na-K-Cl Cotransporter Reduces Edema Formation in the Rat Middle Cerebral Artery Occlusion Model of Stroke

O’Donnell

Tran

Lam

et al. 2004

J Cereb Blood Flow Metab

222

258

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Summary:Increased transport of Na + across an intact bloodbrain barrier (BBB) participates in edema formation during the early hours of cerebral ischemia. In previous studies, the authors showed that the BBB Na-K-Cl cotransporter is stimulated by factors present during ischemia, suggesting that the cotransporter may contribute to the increased brain Na + uptake in edema. The present study was conducted to determine (1) whether the Na-K-Cl cotransporter is located in the luminal membrane of the BBB, and (2) whether inhibition of the BBB cotransporter reduces brain edema formation. Perfusion-fixed rat brains were examined for cotransporter distribution by immunoelectron microscopy. Cerebral edema was evaluated in rats subjected to permanent middle cerebral artery occlusion (MCAO) by magnetic resonance diffusion-weighted imaging and calculation of apparent diffusion coefficients (ADC). The immunoelectron microscopy studies revealed a predominant (80%) luminal membrane distribution of the cotransporter. Magnetic resonance imaging studies showed ADC ratios (ipsilateral MCAO/contralateral control) ranging from 0.577 to 0.637 in cortex and striatum, indicating substantial edema formation. Intravenous bumetanide (7.6-30.4 mg/kg) given immediately before occlusion attenuated the decrease in ADC ratios for both cortex and striatum (by 40-67%), indicating reduced edema formation. Bumetanide also reduced infarct size, determined by TTC staining. These findings suggest that a luminal BBB Na-K-Cl cotransporter contributes to edema formation during cerebral ischemia. Key Words: Cotransport-Blood-brain barrier-Stroke, Cerebral ischemiaCerebral edema-Bumetanide.Brain edema that forms during the early hours of ischemic stroke involves a net uptake of Na + and water from blood into brain across an intact blood-brain barrier

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Section: Discussionmentioning

confidence: 99%

Bumetanide Inhibition of the Blood-Brain Barrier Na-K-Cl Cotransporter Reduces Edema Formation in the Rat Middle Cerebral Artery Occlusion Model of Stroke

O’Donnell

Tran

Lam

et al. 2004

J Cereb Blood Flow Metab

222

258

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“…First, the activities of many membrane solute transporters change with the oxygen content of the cell, including volume regulatory transporters (eg, Na ϩ /H ϩ exchanger), cation coupled Cl Ϫ cotransporters, amino acid transporters, and ion channels. [1][2][3][4][5][6][7][8][9][10] The K/Cl cotransporter, for example, is reported to be 20-fold more active in oxygenated than in deoxygenated RBCs. 9,10 Second, erythrocyte metabolism is modulated by the O 2 tension of the medium.…”

Section: Introductionmentioning

confidence: 99%

Characterization of the deoxyhemoglobin binding site on human erythrocyte band 3: implications for O2 regulation of erythrocyte properties

Chu

Breite

Ciraolo

et al. 2008

Blood

108

131

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Band 3, the major protein of the human erythrocyte membrane, associates with multiple metabolic, ion transport, and structural proteins. Functional studies demonstrate that the oxygenation state of the erythrocyte regulates cellular properties performed by these and/or related proteins. Because deoxyhemoglobin, but not oxyhemoglobin, binds band 3 reversibly with high affinity, these observations raise the hypothesis that hemoglobin might regulate erythrocyte properties through its reversible, oxygenationdependent association with band 3. To explore this hypothesis, we have characterized the binding site of deoxyHb on human erythrocyte band 3. We report that (1) deoxyHb binds to residues 12-23 of band 3; (2) mutation of residues on either side of this sequence greatly enhances affinity of deoxyHb for band 3, suggesting that evolution of a higher affinity interaction would have been possible had it been beneficial for survival; (3) Hb does not bind to 2 other sequences in band 3 despite their high sequence homology to residues 12-23, and (4) IntroductionSeveral lines of evidence suggest that the oxygenation state of the erythrocyte (RBC) regulates multiple erythrocyte properties. First, the activities of many membrane solute transporters change with the oxygen content of the cell, including volume regulatory transporters (eg, Na ϩ /H ϩ exchanger), cation coupled Cl Ϫ cotransporters, amino acid transporters, and ion channels. [1][2][3][4][5][6][7][8][9][10] The K/Cl cotransporter, for example, is reported to be 20-fold more active in oxygenated than in deoxygenated RBCs. 9,10 Second, erythrocyte metabolism is modulated by the O 2 tension of the medium. Thus, glucose flux through the pentose phosphate pathway proceeds twice as rapidly in oxygenated as in deoxygenated cells, and glucose consumption in glycolysis is inhibited by oxygenation. 11 Third, erythrocyte deoxygenation may affect membrane structural properties. For example, deoxygenated hemoglobin (Hb) (but not oxygenated Hb [oxyHb]) competes with ankyrin for binding to band 3, and band 3 retention in detergent-extracted membrane skeletons is greatly reduced in skeletal pellets from deoxygenated cells (M. Stefanovic and P.S.L., unpublished data, December 2005). Furthermore, ankyrin epitopes are more accessible to antiankyrin antibodies in deoxygenated than in oxygenated RBCs. Taken together, these latter findings imply a looser association of ankyrin with the membrane in deoxygenated than in oxygenated erythrocytes.In searching for a mechanism to account for oxygenation effects on red cell properties, identification of both the O 2 sensor and downstream effector was considered important. A major candidate for the O 2 sensor was presumed to be Hb, because the O 2 dependence of the above properties generally follows the O 2 dissociation curve of Hb. 4,12,13 The downstream effector has been more uncertain, but band 3 has represented the prime candidate, because it constitutes the only established binding site of Hb on the membrane. Moreover, multiple observation...

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“…In rainbow trout, the effect of oxygen on transporter activity seems to be mediated through hydroxyl radicals, which stimulate KCC activity, whilst they inhibit the ␤NHE at high P O 2 (Bogdanova and Nikinmaa, 2001;Nikinmaa et al, 2003). The oxygen dependency of NKCC activity in RBCs of some tetrapods such as turkey and ferret and in crucian carp, however, is consistent with modulation by the Hb oxygenation state (Muzyamba et al, 1999;Flatman, 2005;Berenbrink et al, 2006). Shrinkage of B. marinus RBCs was attended by a pronounced amiloride-sensitive RVI response (Fig.·3C, Fig.·4C) that was much faster under deoxygenated conditions (Fig.·3B), reflecting the time course of activation and the magnitude of the Na influxes under the two levels of P O 2 (Fig.·1).…”

Section: Discussionmentioning

confidence: 77%

“…P O 2 dependency of shrinkage-induced Na influx and RVI Oxygenation-dependent RBC membrane transporters have now been described in nearly all vertebrate classes, ranging from lamprey to mammals (Motais et al, 1987;Nielsen et al, 1992;Gibson et al, 1998;Virkki et al, 1998;Muzyamba et al, 1999;Berenbrink et al, 2000;Berenbrink et al, 2006;Flatman, 2005) (reviewed by Gibson et al, 2000). This also applies to the transporters involved in volume regulation (Jensen, 1995;Nielsen, 1997;Gibson et al, 2000;Brauner et al, 2002;Drew et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…The regulatory volume increase (RVI) in RBCs from mammals, most teleosts and amphibians is mediated by increased NHE activity, resulting in a net gain of inorganic osmolytes followed by osmotically obliged water (Cala, 1980;Parker et al, 1991;Orlov et al, 1994;Romero et al, 1996;Gusev et al, 1997;Weaver et al, 1999) whereas bird RBCs activate the NKCC (Kregenow, 1981;Muzyamba et al, 1999). In addition to shrinkage, the activity of the NHE and NKCC and other RBC ion transporters is modulated by oxygen, catecholamines or acidification [NHE (Motais et al, 1987;Salama and Nikinmaa, 1988;Nielsen, 1997;Virkki et al, 1998) and NKCC Muzyamba et al, 1999;Flatman, 2005;Berenbrink et al, 2006)]. Thus, in various vertebrates, the NHE, NKCC and/or RVI response are inhibited in airequilibrated cells compared with cells at low oxygen partial pressure (P O 2) (Gibson et al, 2000;Brauner et al, 2002;Jensen et al, 2002;Drew et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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Oxygen-sensitive regulatory volume increase and Na transport in red blood cells from the cane toad,Bufo marinus

Kristensen

Koldkjær

Berenbrink

et al. 2007

Journal of Experimental Biology

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SUMMARY The red blood cells (RBCs) of cane toad, Bufo marinus, are only partially saturated with oxygen in most of the circulation due to cardiac shunts that cause desaturation of arterial blood. The present study examines the oxygen dependency of RBC ouabain-insensitive unidirectional Na transport,using 22Na, in control cells and in cells exposed to hyperosmotic shrinkage or the β-adrenergic agonist isoproterenol. Deoxygenation per se induced a slow, but significant Na influx, which was paralleled by a slow increase in RBC volume. Hyperosmotic shrinkage by a calculated 25% activated a robust Na influx that in the first 30 min had a strong PO2 dependency with maximal activation at low PO2 values and a P50of ∼5.5 kPa. This activation was completely abolished by the Na/H exchanger (NHE) inhibitor EIPA (10–4 mol l-1). Hyperosmotic shrinkage is particularly interesting in B. marinus as it withstands considerable elevation in extracellular osmolarity following dehydration. Parallel studies showed that deoxygenated B. marinusRBCs had a much faster regulatory volume increase (RVI) response than air-equilibrated RBCs, reflecting the difference in magnitude of Na influxes at the two PO2 values. The extent of RVI(∼60%) after 90 min, however, was similar under the two conditions,reflecting a more prolonged elevation of the shrinkage-induced Na influx in air-equilibrated RBCs. There were no significant differences in the ability to perform RVI between whole blood cells at a PCO2of 1 and 3 kPa or washed RBCs, and 10–4 mol l-1amiloride reduced the RVI under all conditions, whereas 10–5mol l-1 bumetanide had no effect. Isoproterenol(10–5 mol l-1) induced a significant and prolonged increase in an EIPA-sensitive and bumetanide-insensitive Na influx at low PO2 under iso-osmotic conditions, whilst there was no stimulation by isoproterenol for up to 45 min in air-equilibrated RBCs. The prolonged β-adrenergic activation of the Na influx at low PO2 is distinctly different from the rapid and transient stimulation in teleost RBCs, suggesting significant differences in the signal transduction pathways leading to transporter activation between vertebrate groups.

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Regulation of Na⁺‐K⁺‐2Cl⁻ cotransport in turkey red cells: the role of oxygen tension and protein phosphorylation

Cited by 52 publications

References 42 publications

Bumetanide Inhibition of the Blood-Brain Barrier Na-K-Cl Cotransporter Reduces Edema Formation in the Rat Middle Cerebral Artery Occlusion Model of Stroke

Bumetanide Inhibition of the Blood-Brain Barrier Na-K-Cl Cotransporter Reduces Edema Formation in the Rat Middle Cerebral Artery Occlusion Model of Stroke

Characterization of the deoxyhemoglobin binding site on human erythrocyte band 3: implications for O2 regulation of erythrocyte properties

Oxygen-sensitive regulatory volume increase and Na transport in red blood cells from the cane toad,Bufo marinus

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