Importance of K+-dependent Na+/Ca2+-exchanger 2, NCKX2, in Motor Learning and Memory

Li, Xiao Fang; Kiedrowski, Lech; Tremblay, François; Fernandez, Fernando R.; Perizzolo, Marco; Winkfein, Robert J.; Turner, Ray W.; Bains, Jaideep S.; Rancourt, Derrick E.; Lytton, Jonathan

doi:10.1074/jbc.m512137200

Cited by 85 publications

(77 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Inactivation of NCKX2 may be a useful regulatory mechanism that operates under physiological conditions. Mounting evidence points to NCKX2 being an important Ca 2ϩ clearance mechanism in neuronal synaptic terminals (13)(14)(15), which are specialized compartments that experience frequent and dynamic Ca 2ϩ fluxes and depolarized membrane potential resulting from frequent invasions of action potential spikes. Persistent presynaptic activity leads to persistent elevations in presynaptic terminal Ca 2ϩ concentrations (43,44), associated with an increase in intraterminal Na ϩ levels (up to peaks of 80 mM) (45).…”

Section: Controlling Alkali Cation Concentrations Using Gramicidin-mentioning

confidence: 99%

“…The Na ϩ /Ca 2ϩ -K ϩ exchanger (NCKX) NCKX1 was first reported in retinal rod outer segments and is the isoform on which most extensive physiological studies have been performed (6 -8). NCKX2 transcripts have been reported in the brain and retina (9 -12), and recent emergent evidence indicates that this isoform is important for regulation of Ca 2ϩ levels in synaptic terminals (13)(14)(15). NCKX3 and NCKX4 transcripts are also found in the brain, but have also been localized to smooth muscle of the aorta, uterus, and intestine (16,17).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Na+-dependent Inactivation of the Retinal Cone/Brain Na+/Ca2+-K+ Exchanger NCKX2

Altimimi

Schnetkamp

2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

The SLC24 gene family Na ؉ /Ca 2؉ -K ؉ exchangers (NCKX) are bidirectional plasma membrane transporters whose main function is the extrusion of Ca 2؉ from the cytosol. In this study, we used human embryonic kidney 293 cells expressing human retinal cone/brain NCKX2 to examine its Na ؉ affinity and kinetic parameters of Ca 2؉ transport. With the use of the ionophore gramicidin to control alkali cation concentrations across the plasma membrane, application of high intracellular Na ؉ promoted large NCKX2-mediated increases in intracellular free Ca 2؉ in the 15-20 M range; this also resulted in inactivation of NCKX2 transport, the first description of this novel kinetic state. The affinity of NCKX2 for internal Na ؉ was found to be sigmoidal, with a Hill coefficient of 2.6 and K d ‫؍‬ 50 mM. The time-dependent (t1 ⁄ 2 ϳ 40s) inactivation of NCKX2 required high intracellular Na ؉ levels (K d > 50 mM) as well as high occupancy of the extracellular Ca 2؉ -binding site. Also reported are two residues whose substitution resulted in an increase in internal Na ؉ affinity to values of ϳ19 mM; these mutants also displayed enhanced inactivation, suggesting that inactivation requires binding of Na ؉ to its intracellular transport sites. These findings are the first report of a regulatory kinetic state of Ca 2؉ transport via NCKX2 Na ؉ /Ca 2؉ -K ؉ exchangers that may play a prominent role in regulation of Ca 2؉ extrusion in cellular environments such as neuronal synapses that experience frequent and dynamic Ca 2؉ fluxes.

show abstract

Section: Controlling Alkali Cation Concentrations Using Gramicidin-mentioning

confidence: 99%

mentioning

confidence: 99%

Na+-dependent Inactivation of the Retinal Cone/Brain Na+/Ca2+-K+ Exchanger NCKX2

Altimimi

Schnetkamp

2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…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.

View full text Add to dashboard Cite

, 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.

show abstract

“…An NCKX2 paralog was also recently cloned from the retina of striped bass, and isolated cone outer segments were shown to contain K + -dependent Na + /Ca 2+ exchange activity (45). However, NCKX2 knockout mice did not display any obvious deficits in either cone number or function, suggesting that either other Ca 2+ efflux pathways compensated for the absence of NCKX2 or that NCKX function plays a more subtle role in Ca 2+ homeostasis in cone photoreceptors that would require more detailed analyses to elucidate (35).…”

Section: Structure and Functionmentioning

confidence: 99%

“…The results of these studies have demonstrated that NCKX proteins play important functional roles in neuronal Ca 2+ signaling, although the precise impact of these exchangers on neuronal function is only beginning to be elucidated. Recently, knockout mice lacking NCKX2 were shown to display deficits in motor learning and memory that could be attributed to compromised hippocampal synaptic plasticity (35). Future studies on acute brain preparations and cultured neurons from mice lacking specific NCKX isoforms will more clearly define their functional roles in Ca 2+ signaling and the subsequent impact on neuronal function.…”

Section: Neuronal Physiologymentioning

confidence: 99%

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

Visser

Lytton

2007

Physiology

Self Cite

View full text Add to dashboard Cite

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...

show abstract

Importance of K+-dependent Na+/Ca2+-exchanger 2, NCKX2, in Motor Learning and Memory

Cited by 85 publications

References 62 publications

Na+-dependent Inactivation of the Retinal Cone/Brain Na+/Ca2+-K+ Exchanger NCKX2

Na+-dependent Inactivation of the Retinal Cone/Brain Na+/Ca2+-K+ Exchanger NCKX2

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

Contact Info

Product

Resources

About

Importance of K+-dependent Na+/Ca2+-exchanger 2, NCKX2, in Motor Learning and Memory

Cited by 85 publications

References 62 publications

Na+-dependent Inactivation of the Retinal Cone/Brain Na+/Ca2+-K+ Exchanger NCKX2

Na+-dependent Inactivation of the Retinal Cone/Brain Na+/Ca2+-K+ Exchanger NCKX2

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

Contact Info

Product

Resources

About

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