Electrophysiological Characterization and Ionic Stoichiometry of the Rat Brain K+-dependent Na+/Ca2+ Exchanger, NCKX2

Dong, Hui; Light, Peter E.; French, Robert J.; Lytton, Jonathan

doi:10.1074/jbc.m103401200

Cited by 59 publications

(58 citation statements)

References 46 publications

(47 reference statements)

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“…In situ studies on the properties of the NCKX cation transport sites have only been carried out on the NCKX1 exchanger in retinal rod outer segments (reviewed in Refs. 4,15,16), while several studies have reported on the cation concentration dependence of heterologously expressed NCKX1 (dolphin, chicken), NCKX2 (chicken, human, rat), Caenorhabditis elegans NCKX, and a NCKX1 deletion mutant from which the two large hydrophilic loops (ϳ63% of the total sequence) were removed (9,13,14,17,18). The values obtained in situ for NCKX1 and in heterologous systems for the various NCKX isoforms mentioned above were quite similar.…”

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confidence: 49%

“…The first four mammalian NCKX isoforms and those cloned from lower organisms have been shown to code for K ϩ -dependent Na ϩ /Ca 2ϩ exchangers when expressed in cell lines and transcripts are found in a wide variety of tissues (2). NCKX1 and NCKX2 carry out K ϩ and Ca 2ϩ cotransport and Na ϩ and Ca 2ϩ countertransport at a stoichiometry of 4Na ϩ : 1Ca 2ϩ ϩ 1K ϩ (3,13,14). This study concerns identification of residues involved in cation transport via the NCKX Na ϩ /Ca 2ϩ -K ϩ exchanger.…”

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confidence: 99%

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Residues Contributing to the Ca2+ and K+ Binding Pocket of the NCKX2 Na+/Ca2+-K+ Exchanger

Kang¹,

Kinjo²,

Szerencsei

et al. 2005

Journal of Biological Chemistry

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confidence: 49%

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confidence: 99%

Residues Contributing to the Ca2+ and K+ Binding Pocket of the NCKX2 Na+/Ca2+-K+ Exchanger

Kang¹,

Kinjo²,

Szerencsei

et al. 2005

Journal of Biological Chemistry

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“…Reverse and forward I NCKX were recorded using a holding potential of 0 mV. The I NCKX was recorded, according to Dong et al (2001), starting from a holding potential of 0 mV to a short-step depolarization at ϩ80 mV (60 ms). Then, a descending voltage ramp from ϩ80 mV to Ϫ80 mV was applied.…”

Section: Electrophysiologymentioning

confidence: 99%

“…NCKX2, NCKX3, and NCKX4 are broadly expressed in brain with distinct, often overlapping, regional distributions . The expression of NCKX2, the major neuronally expressed isoform (Tsoi et al, 1998;Dong et al, 2001), is limited to cone photoreceptors (Prinsen et al, 2000) and to neurons, where it plays important physiological roles (Tsoi et al, 1998;Li et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

A Critical Role for the Potassium-Dependent Sodium–Calcium Exchanger NCKX2 in Protection against Focal Ischemic Brain Damage

Cuomo¹,

Gala²,

Pignataro³

et al. 2008

J. Neurosci.

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, and K ϩ homeostasis in the CNS, the role of NCKX2 during cerebral ischemia, a condition characterized by an alteration of ionic concentrations, has not yet been investigated. The present study examines NCKX2 role in the development of ischemic brain damage in permanent middle cerebral artery occlusion (pMCAO) and transient middle cerebral artery occlusion. Furthermore, to evaluate the effect of nckx2 ablation on neuronal survival, nckx2؊/؊ primary cortical neurons were subjected to oxygen glucose deprivation plus reoxygenation. NCKX2 mRNA and protein expression was evaluated in the ischemic core and surrounding ipsilesional areas, at different time points after pMCAO in rats. In ischemic core and in periinfarctual area, NCKX2 mRNA and protein expression were downregulated. In addition, NCKX2 knock-down by antisense oligodeoxynucleotide and NCKX2 knock-out by genetic disruption dramatically increased infarct volume. Accordingly, nckx2؊/؊ primary cortical neurons displayed a higher vulnerability and a greater [Ca 2ϩ ] i increase under hypoxic conditions, compared with nckx2؉/؉ neurons. In addition, NCKX currents both in the forward and reverse mode of operation were significantly reduced in nckx2؊/؊ neurons compared with nckx2؉/؉ cells. Overall, these results indicate that NCKX2 is involved in brain ischemia, and it may represent a new potential target to be investigated in the study of the molecular mechanisms involved in cerebral ischemia.

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“…These functional properties were subsequently confirmed for recombinant NCKX1 and 2 using either 45 Ca 2+ uptake into insect cells or electrophysiological recordings in HEK293 cells (11,55,57). Furthermore, NCKX1 and 2 display similar apparent affinities for Ca 2+ (~1-2 M), K + (15-40 mM), and Na + (20-60 mM) (11,47). Based on sequence identity, the other NCKX family members are expected to display the same stoichiometry.…”

Section: Structure and Functionmentioning

confidence: 70%

K⁺-Dependent Na⁺/Ca²⁺Exchangers: Key Contributors to Ca²⁺Signaling

Visser

Lytton

2007

Physiology

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Ca 2+ acts as a ubiquitous second messenger to control a wide variety of physiological processes by relaying information within mammalian cells (6). For example, Ca 2+ signals trigger fertilization, control development and differentiation, coordinate cellular functions, and even play roles in cell death. The large variety of functional effects are dictated by the spatial and temporal nature of the Ca 2+ signals and by the cellular context in which they occur, that is, the tissue and cell-specific complement of Ca 2+ influx/efflux pathways and downstream targets determine the final outcome. Cytosolic Ca 2+ influx typically occurs when Ca 2+ channels localized to the plasma or endoplasmic reticular membranes open in response to various stimuli such as membrane depolarization or ligand binding (5). Ca 2+ can be subsequently removed from the cytosol by various mechanisms: sarco/endoplasmic reticulum Ca 2+ ATPases (SERCA) and plasma membrane Ca 2+ ATPases (PMCA) utilize the energy from ATP hydrolysis to pump Ca 2+ into the endoplasmic reticulum or outside the cell, respectively, and Na + /Ca 2+ exchangers extrude cytosolic Ca 2+ in exchange for extracellular Na + . In certain cellular contexts, such as localized signals in the dendritic spines of neurons, Ca 2+ flux across the plasma membrane predominates over that from intracellular stores (2, 49). In such cases, PMCA proteins control the resting Ca 2+ concentrations because of their high-affinity/lowcapacity transport properties, whereas Na + /Ca 2+ exchangers display low-affinity/high-capacity transport properties that are ideally suited for cytosolic clearance when Ca 2+ is elevated following a signaling event. Detailed knowledge of the physiological and biochemical properties of calcium channels and transporters is critical to understanding the mechanisms of Ca 2+ signaling in various cellular contexts. This review will focus on recent progress in the understanding of the physiology, function, structure, and regulation of the recently identified family of K + -dependent Na + /Ca 2+ exchangers. K + -Dependent and Independent Na + /Ca 2+ ExchangersThere are two families of Na + /Ca 2+ exchangers in mammalian cells: those that are K + -dependent (NCKX) and those that are K + -independent (NCX). Physiologically, NCX proteins function by extruding cytosolic Ca 2+ in exchange for extracellular Na + ions, whereas NCKX proteins extrude cytosolic Ca 2+ and K + in exchange for Na + ions, which in both cases is referred to as forward mode exchange. In conditions of altered ion gradients and membrane potential, these exchangers can also mediate Ca 2+ entry or so-called reverse mode operation. Three NCX and five NCKX isoforms have been identified by molecular cloning. NCX1 is predominantly expressed in the heart, brain, and kidney, although it is also present in a broad variety of cell types, whereas NCX2 and 3 expression is limited to brain and skeletal muscle (38,42,43). NCKX1 is exclusively expressed in retinal rod outer segments, whereas NCKX2 is expressed in brain and c...

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Electrophysiological Characterization and Ionic Stoichiometry of the Rat Brain K+-dependent Na+/Ca2+ Exchanger, NCKX2

Cited by 59 publications

References 46 publications

Residues Contributing to the Ca2+ and K+ Binding Pocket of the NCKX2 Na+/Ca2+-K+ Exchanger

Residues Contributing to the Ca2+ and K+ Binding Pocket of the NCKX2 Na+/Ca2+-K+ Exchanger

A Critical Role for the Potassium-Dependent Sodium–Calcium Exchanger NCKX2 in Protection against Focal Ischemic Brain Damage

K⁺-Dependent Na⁺/Ca²⁺Exchangers: Key Contributors to Ca²⁺Signaling

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Electrophysiological Characterization and Ionic Stoichiometry of the Rat Brain K+-dependent Na+/Ca2+ Exchanger, NCKX2

Cited by 59 publications

References 46 publications

Residues Contributing to the Ca2+ and K+ Binding Pocket of the NCKX2 Na+/Ca2+-K+ Exchanger

Residues Contributing to the Ca2+ and K+ Binding Pocket of the NCKX2 Na+/Ca2+-K+ Exchanger

A Critical Role for the Potassium-Dependent Sodium–Calcium Exchanger NCKX2 in Protection against Focal Ischemic Brain Damage

K+-Dependent Na+/Ca2+Exchangers: Key Contributors to Ca2+Signaling

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K⁺-Dependent Na⁺/Ca²⁺Exchangers: Key Contributors to Ca²⁺Signaling