Erythrocyte K-Cl cotransport: properties and regulation

Lauf, Peter K.; Bauer, Johann; Adragna, Norma C.; Fujise, Hiroshi; Zade-Oppen, A. M. M.; Ryu, K. H.; Delpire, Eric

doi:10.1152/ajpcell.1992.263.5.c917

Cited by 242 publications

(202 citation statements)

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“…Characterization of the K + influx via KCC and KNHE in the CHC patient's erythrocytes showed that the unusually high cation permeability in these cells at low temperature is, at least in part, a cumulative effect of an abnormal activation of two independent ion transport systems: KCC and KNHE. As follows from the Table 1, and in agreement with former reports, 22,30 both ion transporters are almost silent in RBC from healthy donors (and the patient's family members), particularly during cold storage. Several lines of evidence point towards an abnormally high activity of the cation-proton exchanger in RBC of the CHC patient at 37°C and even more so at 0°C.…”

Section: Discussionsupporting

confidence: 91%

Cryohydrocytosis: increased activity of cation carriers in red cells from a patient with a band 3 mutation

Bogdanova

Goede²,

Weiss³

et al. 2009

Haematologica

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BackgroundCryohydrocytosis is an inherited dominant hemolytic anemia characterized by mutations in a transmembrane segment of the anion exchanger (band 3 protein). Transfection experiments performed in Xenopus oocytes suggested that these mutations may convert the anion exchanger into a non-selective cation channel. The present study was performed to characterize so far unexplored ion transport pathways that may render erythrocytes of a single cryohydrocytosis patient cation-leaky. Design and MethodsCold-induced changes in cell volume were monitored using ektacytometry and density gradient centrifugation. Kinetics, temperature and inhibitor-dependence of the cation and water movements in the cryohydrocytosis patient's erythrocytes were studied using radioactive tracers and flame photometry. Response of the membrane potential of the patient's erythrocyte membrane to the presence of ionophores and blockers of anion and cation channels was assessed. ResultsIn the cold, the cryohydrocytosis patient's erythrocytes swelled in KCl-containing, but not in NaCl-containing or KNO3-containing media indicating that volume changes were mediated by an anion-coupled cation transporter. In NaCl-containing medium the net HOE-642-sensitive Na + /K + exchange prevailed, whereas in KCl-containing medium swelling was mediated by a chloride-dependent K + uptake. Unidirectional K + influx measurements showed that the patient's cells have abnormally high activities of the cation-proton exchanger and the K + ,Cl -co-transporter, which can account for the observed net movements of cations. Finally, neither chloride nor cation conductance in the patient's erythrocytes differed from that of healthy donors. ConclusionsThese results suggest that cross-talk between the mutated band 3 and other transporters might increase the cation permeability in cryohydrocytosis.

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Section: Discussionsupporting

confidence: 91%

Cryohydrocytosis: increased activity of cation carriers in red cells from a patient with a band 3 mutation

Bogdanova

Goede²,

Weiss³

et al. 2009

Haematologica

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“…LK sheep red cells are the more unusual in having a high passive K¤ 'leak' coupled with a small active K¤ uptake through the Na¤,K¤-ATPase (Tosteson & Hoffman, 1960); the reverse pertains for HK red cells. The large K¤ 'leak' in LK red cells is, in fact, a very specific anion-dependent transporter, exquisitely sensitive to volume, pH and urea (Dunham & Ellory, 1981;Lauf et al 1992 ;Dunham, 1995). It is almost certainly via the KCl cotransporter, recently cloned from human, rat and rabbit tissues (Gillen, Brill, Payne & Forbush, 1996).…”

Section: Discussionmentioning

confidence: 99%

“…The subsequent change in free [Mg¥]é may interact with the complex PPÏPK cascade regulating cotransport activity at several points (Lauf, Erdmann & Adragna, 1994;Flatman et al 1996). Certainly Mg¥ depletion or loading of red cells modulates cotransport activity (Delpire & Lauf, 1991;Lauf et al 1992) and, furthermore, changes in POµ are unable to alter cotransport activity in the absence of functioning PPÏPK enzymes (trout - Cossins, Weaver, Lykkeboe & Nielsen, 1994;horseHoness et al 1996). Pharmacologically, however, the sensitivity of the cotransporter to magnesium is low (Delpire & Lauf, 1991;Lauf et al 1992), and there is no definitive evidence that the magnitude of Oµ-dependent (physiological) flucations in free [Mg¥]é per se is sufficient to modulate cotransport activity.…”

Section: Intracellular Magnesium and Oµ Dependency Of K¤ Influxesmentioning

confidence: 99%

“…Certainly Mg¥ depletion or loading of red cells modulates cotransport activity (Delpire & Lauf, 1991;Lauf et al 1992) and, furthermore, changes in POµ are unable to alter cotransport activity in the absence of functioning PPÏPK enzymes (trout - Cossins, Weaver, Lykkeboe & Nielsen, 1994;horseHoness et al 1996). Pharmacologically, however, the sensitivity of the cotransporter to magnesium is low (Delpire & Lauf, 1991;Lauf et al 1992), and there is no definitive evidence that the magnitude of Oµ-dependent (physiological) flucations in free [Mg¥]é per se is sufficient to modulate cotransport activity. Mature sheep red cells lack most organic phosphates (notably DPG) which modulate the Oµ affinity of haemoglobin in red cells of other mammalian species and lower vertebrates (e.g.…”

Section: Intracellular Magnesium and Oµ Dependency Of K¤ Influxesmentioning

confidence: 99%

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Oxygen‐dependent K⁺ fluxes in sheep red cells

Campbell

Gibson

1998

The Journal of Physiology

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This study was designed to investigate the O2 dependence of K+ influx in sheep red cells. Influx was determined using 86Rb+ as a tracer for K+; glass tonometers coupled to a gas mixing pump were used to equilibrate cell samples to the requisite oxygen tension (PO2). Both volume‐ and H+‐stimulated K+ influxes in low potassium‐containing (LK) sheep red cells were approximately doubled on equilibration with O2 relative to influxes measured in N2. O2‐dependent influxes were abolished when Cl− was replaced with NO3−, consistent with mediation by the KCl cotransporter. At pH 7, PO2 required for half‐maximal stimulation was 56 ± 1 mmHg (mean ± s.e.m., 3 sheep) for the O2‐dependent component of K+ influx: thus PO2 values over the physiological range affected K+ influx. K+ influx in fully deoxygenated sheep red cells showed substantial volume and H+ sensitivity. These residual components in N2 were also Cl− dependent, indicating that the KCl cotransporter of LK sheep red cells was active in the absence of O2. Volume‐sensitive K+ influxes in high potassium‐containing (HK) sheep red cells responded in a similar way to those in cells from LK sheep, although much smaller in magnitude, showing that intracellular [K+] had no significant effect on the O2 dependence of the cotransporter. Intracellular [Mg2+] ([Mg2+]i) was altered by incubating sheep red cells with A23187 (20 μM) and different values of extracellular [Mg2+] ([Mg2+]o). Total [Mg2+]i was determined by atomic absorption spectroscopy and free [Mg2+]i from [Mg2+]o and the Donnan ratio. Total [Mg2+]i was 1.29 ± 0.08 mM (mean ± s.e.m., n= 5), similar to that reported in the literature. Estimates of free [Mg2+]i showed an increase from 0.39 ± 0.05 in oxygenated cells to 0.52 ± 0.04 mM (mean ± s.e.m., n= 5; P < 0.05) in deoxygenated ones. Finally, although K+ influxes were altered by pharmacological loading or depletion of cells with Mg2+, the free [Mg2+]i required to affect influxes significantly was outside the physiological range. Results are difficult to reconcile with PO2 modulating KCl cotransport activity directly via changes in free [Mg2+]i or [Mg2+‐ATP]i.

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“…For this reason, and given that K ϩ -Cl Ϫ cotransport is enhanced under conditions that lead to cell swelling, the KCCs are believed to play a key role in regulatory volume decrease responses (15)(16)(17). However, K ϩ -Cl Ϫ cotransport is not completely abolished under isotonic conditions (18 -20) 4 and is sensitive to changes in intracellular ionic strength (21)(22)(23), suggesting that the KCCs are also of central importance in intracellular Cl Ϫ (Cl i Ϫ ) regulation (22,23) and can thus affect a variety of physiological processes (24 -26).…”

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confidence: 99%

Identification of Key Functional Domains in the C Terminus of the K+-Cl– Cotransporters

Bergeron¹,

Gagnon²,

Caron

et al. 2006

Journal of Biological Chemistry

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The K؉ -Cl ؊ cotransporter (KCC) isoforms constitute a functionally heterogeneous group of ion carriers. Emerging evidence suggests that the C terminus (Ct) of these proteins is important in conveying isoform-specific traits and that it may harbor interacting sites for 4␤-phorbol 12-myristate 13-acetate (PMA)-induced effectors. In this study, we have generated KCC2-KCC4 chimeras to identify key functional domains in the Ct of these carriers and single point mutations to determine whether canonical protein kinase C sites underlie KCC2-specific behaviors. Functional characterization of wild-type (wt) and mutant carriers in Xenopus laevis oocytes showed for the first time that the KCCs do not exhibit similar sensitivities to changes in osmolality and that this distinguishing feature as well as differences in transport activity under both hypotonic and isotonic conditions are in part determined by the residue composition of the distal Ct. At the same time, several mutations in this domain and in the proximal Ct of the KCCs were found to generate allosteric-like effects, suggesting that the regions analyzed are important in defining conformational ensembles and that isoform-specific structural configurations could thus account for variant functional traits as well. Characterization of the other mutants in this work showed that KCC2 is not inhibited by PMA through phosphorylation of its canonical protein kinase C sites. Intriguingly, however, the substitutions N728S and S940A were seen to alter the PMA effect paradoxically, suggesting again that allosteric changes in the Ct are important determinants of transport activity and, furthermore, that the structural configuration of this domain can convey specific functional traits by defining the accessibility of cotransporter sites to regulatory intermediates such as PMAinduced effectors.The cation-Cl Ϫ cotransporter (CCC) 3 family includes Na ϩ -dependent and Na ϩ -independent ion carriers (1-8). The latter group is con- (25,26). The importance of the KCCs in these processes is suggested more specifically by the behavior of a KCC4 Ϫ/Ϫ mouse, which was found to exhibit renal tubular acidosis (24), and a KCC2 Ϫ/Ϫ mouse, which was found to exhibit generalized epilepsy (26). The mechanisms that lead to KCC deactivation or activation during a change in cell volume and Cl i Ϫ are still poorly understood despite a large number of studies on the subject of K ϩ -Cl Ϫ cotransport regulation.Based on the effect of various pharmacological agents, a popular model that has emerged over the years is one in which K ϩ -Cl Ϫ cotransport is reduced through carrier phosphorylation and induced through carrier dephosphorylation, and in which such modifications result from the concerted action of protein kinases and protein phosphatases at relevant regulatory sites (14 -17, 27-36). It should be mentioned, however, that most of these studies have addressed the issue of cell volume-dependent, rather than Cl i Ϫ -dependent regulation.Although different types of protein phosphatase and kinases tha...

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Erythrocyte K-Cl cotransport: properties and regulation

Cited by 242 publications

References 99 publications

Cryohydrocytosis: increased activity of cation carriers in red cells from a patient with a band 3 mutation

Cryohydrocytosis: increased activity of cation carriers in red cells from a patient with a band 3 mutation

Oxygen‐dependent K⁺ fluxes in sheep red cells

Identification of Key Functional Domains in the C Terminus of the K+-Cl– Cotransporters

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Erythrocyte K-Cl cotransport: properties and regulation

Cited by 242 publications

References 99 publications

Cryohydrocytosis: increased activity of cation carriers in red cells from a patient with a band 3 mutation

Cryohydrocytosis: increased activity of cation carriers in red cells from a patient with a band 3 mutation

Oxygen‐dependent K+ fluxes in sheep red cells

Identification of Key Functional Domains in the C Terminus of the K+-Cl– Cotransporters

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Oxygen‐dependent K⁺ fluxes in sheep red cells