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NCKX family

Hristina Zhekova, Chunfeng Zhao, Paul P M Schnetkamp, Sergei Yu Noskov
NCKX1-5 are proteins involved in K(+)-dependent Na(+)/Ca(2+) exchange in various signal tissues. Here we present a homology model of NCKX2 based on the crystal structure of the NCX_Mj transporter found in Methanoccocus jannaschii. Molecular dynamics simulations were performed on the resultant wild-type NCKX2 model and two mutants (D548N and D575N) loaded with either four Na(+) ions or one Ca(2+) ion and one K(+) ion, in line with the experimentally observed transport stoichiometry. The selectivity of the active site in wild-type NCKX2 for Na(+), K(+), and Li(+) and the electrostatic interactions of the positive Na(+) ions in the negatively charged active site of wild-type NCKX2 and the two mutants were evaluated from free energy perturbation calculations...
November 22, 2016: Biochemistry
Ali H Jalloul, Tatiana P Rogasevskaia, Robert T Szerencsei, Paul P M Schnetkamp
K(+)-dependent Na(+)/Ca(2+) exchangers belong to the solute carrier 24 (SLC24A1-5) gene family of membrane transporters. Five different gene products (NCKX1-5) have been identified in humans, which play key roles in biological processes including vision, olfaction, and skin pigmentation. NCKXs are bi-directional membrane transporters that transport 1 Ca(2+)+K(+) ions in exchange for 4 Na(+) ions. Recent studies have linked mutations in the SLC24A4 (NCKX4) and SLC24A5 (NCKX5) genes to amylogenesis imperfecta (AI) and non-syndromic oculocutaneous albinism (OCA6), respectively...
June 17, 2016: Journal of Biological Chemistry
Robert T Szerencsei, Rebecca S Ginger, Martin R Green, Paul P M Schnetkamp
The SLC24 gene family encodes K(+)-dependent Na(+)-Ca(2+) exchangers or NCKX proteins. The NCKX4 and NCKX5 isoforms have been shown to be important for pigmentation, and single nucleotide polymorphism (SNP) in both alleles of the SLC24a5 gene is the major genetic determinant for light skin in Caucasians. NCKX4 is thought to operate in the surface membrane of cells, whereas NCKX5 is thought to be located in intracellular membranes. However, no functional data have yet been reported to describe either NCKX4 or NCKX5 activity in pigmented cells...
May 17, 2016: Biochemistry
Vishal Sharma, Damien M O'Halloran
Na(+)/Ca(2+) exchangers are low-affinity, high-capacity transporters that rapidly transport calcium against a gradient of Na(+) ions. Na(+)/Ca(2+) exchangers are divided into three groups based upon substrate specificity: Na(+)/Ca(2+) exchangers (NCX), Na(+)/Ca(2+)/K(+) exchangers (NCKX), and Ca(2+)/cation exchangers (NCLX). In mammals, there are three NCX genes, five NCKX genes, and a single NCLX gene. The genome of the nematode Caenorhabditis elegans contains 10 Na(+)/Ca(2+) exchanger genes: three NCX, five NCLX, and two NCKX genes...
2016: Bioinformatics and Biology Insights
Jon K Pittman, Kendal D Hirschi
BACKGROUND: The Ca(2+)/Cation Antiporter (CaCA) superfamily is an ancient and widespread family of ion-coupled cation transporters found in nearly all kingdoms of life. In animals, K(+)-dependent and K(+)-indendent Na(+)/Ca(2+) exchangers (NCKX and NCX) are important CaCA members. Recently it was proposed that all rice and Arabidopsis CaCA proteins should be classified as NCX proteins. Here we performed phylogenetic analysis of CaCA genes and protein structure homology modelling to further characterise members of this transporter superfamily...
December 2016: Rice
Ali H Jalloul, Robert T Szerencsei, Paul P M Schnetkamp
The Solute Carrier Family 24 (SLC24) belongs to the CaCA super family of Ca(2+)/cation antiporters and codes for five different K(+)- dependent Na(+)- Ca(2+) exchangers (NCKX1-5). NCKX proteins play a critical role in Ca(2+) homeostasis in a wide variety of biological processes such as vision, olfaction, enamel formation, Melanocortin-4-receptor-dependent satiety and skin pigmentation. NCKX transcripts are widely found throughout the brain. In this study we examine the differences between NCKX1-4 in terms of cation dependencies...
January 2016: Cell Calcium
Y Zhang, S Sharma, J Lytton
The K(+)-dependent Na(+)/Ca(2)-exchanger (NCKX) family is encoded by five related genes, of which NCKX2 (solute carrier family 24, member 2) is the most abundant member present in the brain. Nckx2 knockout mice display profound loss of hippocampal long-term potentiation, and selective deficits in motor learning and spatial working memory. However, the molecular mechanisms underlying these changes have not been established. Thus, the overall goal of this project was to identify the exact subcellular localization of NCKX2 in the hippocampus, as an important step toward understanding the physiological role for NCKX2 in neuronal plasticity...
December 3, 2015: Neuroscience
Haifa Hong, Yu Xia, Yanjun Sun, Lincai Ye, Jinfen Liu, Jie Bai, Haibo Zhang
Patency of the ductus arteriosus (DA) after birth is essential in ductal-dependent congenital heart disease. The Na(+)/Ca(2+) exchanger (NCX) has been demonstrated to play a key role in regulating vascular tone. The potassium-dependent Na(+)/Ca(2+) exchanger (NCKX) is a related family of NCX depending on the K(+) gradients which triggers DA constriction. The present study investigated the comparative expression of NCX and NCKX between a constricted DA and patent DA in human ductal-dependant congenital heart disease...
April 2015: Pediatric Cardiology
Paul P M Schnetkamp, Ali H Jalloul, Guohong Liu, Robert T Szerencsei
The human SLC24 gene family contains five members encoding the NCKX1-5 proteins that function as K(+)-dependent Na⁺-Ca²⁺ exchangers. NCKX proteins have been shown to play critical roles in retinal rod and cone photoreceptors, olfactory neurons, epidermal melanocytes, and the retinal pigment epithelium. NCKX transcripts are also found in many other tissues, in particular throughout the brain, but their specific physiological roles yet need to be elucidated in most cases. Here, we focus on our current knowledge of NCKX transport function as has been described in detail only for in situ NCKX1 in the outer segments of retinal rod photoreceptors and on structure-function relationships elucidated for the NCKX2 isoform after expression of its (mutated) cDNA in cell lines...
2014: Current Topics in Membranes
Vishal Sharma, Damien M O'Halloran
Maintenance of calcium homeostasis is necessary for the development and survival of all animals. Calcium ions modulate excitability and bind effectors capable of initiating many processes such as muscular contraction and neurotransmission. However, excessive amounts of calcium in the cytosol or within intracellular calcium stores can trigger apoptotic pathways in cells that have been implicated in cardiac and neuronal pathologies. Accordingly, it is critical for cells to rapidly and effectively regulate calcium levels...
February 2014: Genesis: the Journal of Genetics and Development
Xu Yang, Jonathan Lytton
K+-dependent Na+/Ca2+-exchanger isoform 4 (NCXK4) is one of the most broadly expressed members of the NCKX (K+-dependent Na+/Ca2+-exchanger) family. Recent data indicate that NCKX4 plays a critical role in controlling normal Ca2+ signal dynamics in olfactory and other neurons. Synaptic Ca2+ dynamics are modulated by purinergic regulation, mediated by ATP released from synaptic vesicles or from neighbouring glial cells. Previous studies have focused on modulation of Ca2+ entry pathways that initiate signalling...
2013: Bioscience Reports
Paul P M Schnetkamp
Members of the SLC24 gene family encode K(+)-dependent Na(+)/Ca(2+) exchangers (NCKX) that utilize both the inward Na(+) and outward K(+) gradients to extrude Ca(2+) from cells. There are five human SLC24 genes that play a role in biological process as diverse as vision in retinal rod and cone photoreceptors, olfaction, skin pigmentation and at least three of the five genes are also widely expressed in the brain. Here I review the functional, physiological and structural features of NCKX proteins that have emerged in the past few years...
April 2013: Molecular Aspects of Medicine
Kyu-Hee Lee, Won-Kyung Ho, Suk-Ho Lee
We have previously reported that the surface expression of K(+)-dependent Na(+)/Ca(2+) exchanger 2 (NCKX2) in the somatodendritic compartment is kept low by constitutive endocytosis, which results in the polarization of surface NCKX2 to the axon. Clathrin-mediated endocytosis is initiated by interaction of the μ subunit of adaptor protein complex 2 (AP-2) with the canonical tyrosine motif (YxxΦ) of a target molecule. We examined whether endocytosis of NCKX2 involves two putative tyrosine motifs ((365)YGKL and (371)YDTM) in the cytoplasmic loop of NCKX2...
2013: Frontiers in Cellular Neuroscience
Hyun Yang, Kyung-Chul Choi, Eui-Man Jung, Beum-Soo An, Sang-Hwan Hyun, Eui-Bae Jeung
Plasma membrane sodium/calcium (Na(+)/Ca(2+)) exchangers are an important component of intracellular calcium [Ca(2+)](i) homeostasis and electrical conduction. Na(+)/Ca(2+) exchangers, NCX and NCKX, play a critical role in the transport of one [Ca(2+)](i) and potassium ion across the cell membrane in exchange for four extracellular sodium ions [Na(+)](e). Mammalian plasma membrane Na(+)/Ca(2+) exchange proteins are divided into two families: one in which Ca(2+) flux is dependent only on sodium (NCX1-3) and another in which Ca(2+) flux is also dependent on potassium (NCKX1-4)...
2013: Advances in Experimental Medicine and Biology
Stephen Wilson, Rebecca S Ginger, Tony Dadd, David Gunn, Fei-Ling Lim, Magdalena Sawicka, Melanie Sandel, Paul P M Schnetkamp, Martin R Green
Natural human skin colour is determined both by environmental exposure to ultraviolet light and through inherited genetic variation in a very limited number of genes. Variation of a non-synonymous single-nucleotide polymorphism (nsSNP; rs1426654) in the gene (SLC24A5) encoding the NCKX5 protein is associated with differences in constitutive skin colour in South Asians. The nsSNP encodes the substitution of alanine for threonine at residue 111 (A111T) near a transmembrane region required for exchanger activity, a region which is highly conserved across different species and between NCKX family members...
2013: Advances in Experimental Medicine and Biology
Haider F Altimimi, Robert T Szerencsei, Paul P M Schnetkamp
Na(+)/Ca(2+)-K(+) exchangers (NCKX), alongside the more widely known Na(+)/Ca(2+) exchangers (NCX), are important players in the cellular Ca(2+) toolkit. But, unlike NCX, much less is known about the physiological roles of NCKX, while emergent evidence indicates that NCKX has highly specialized functions in cells and tissues where it is expressed. As their name implies, there are functional similarities in the properties of the two Ca(2+) exchanger families, but there are specific differences as well. Here, we compare and contrast their key functional properties of ionic dependence and affinities, as well as report on the effects of KB-R7943 - a compound that is widely used to differentiate the two exchangers...
2013: Advances in Experimental Medicine and Biology
Ping Hu, Rodrigo S Lacruz, Charles E Smith, Susan M Smith, Ira Kurtz, Michael L Paine
Transcellular calcium transport is an essential activity in mineralized tissue formation, including dental hard tissues. In many organ systems, this activity is regulated by membrane-bound sodium/calcium (Na(+)/Ca(2+)) exchangers, which include the NCX and NCKX [sodium/calcium-potassium (Na(+)/Ca(2+)-K(+)) exchanger] proteins. During enamel maturation, when crystals expand in thickness, Ca(2+) requirements vastly increase but exactly how Ca(2+) traffics through ameloblasts remains uncertain. Previous studies have shown that several NCX proteins are expressed in ameloblasts, although no significant shifts in expression were observed during maturation which pointed to the possible identification of other Ca(2+) membrane transporters...
2012: Cells, Tissues, Organs
Laura Emery, Simon Whelan, Kendal D Hirschi, Jon K Pittman
Cation transport is a critical process in all organisms and is essential for mineral nutrition, ion stress tolerance, and signal transduction. Transporters that are members of the Ca(2+)/cation antiporter (CaCA) superfamily are involved in the transport of Ca(2+) and/or other cations using the counter exchange of another ion such as H(+) or Na(+). The CaCA superfamily has been previously divided into five transporter families: the YRBG, Na(+)/Ca(2+) exchanger (NCX), Na(+)/Ca(2+), K(+) exchanger (NCKX), H(+)/cation exchanger (CAX), and cation/Ca(2+) exchanger (CCX) families, which include the well-characterized NCX and CAX transporters...
2012: Frontiers in Plant Science
Kyu-Hee Lee, Jae Sung Lee, Doyun Lee, Dae-Hyun Seog, Jonathan Lytton, Won-Kyung Ho, Suk-Ho Lee
We have previously shown that K(+)-dependent Na(+)/Ca(2+) exchanger (NCKX) is a major calcium clearance mechanism at the large axon terminals of central neurons, whereas their somata display little NCKX activity. We investigated mechanisms underlying the axonal polarization of NCKX2 in rat hippocampal neurons. We identified NCKX2 as the first neuron-specific cargo molecule of kinesin family member 21A (KIF21A). The intracellular loop of NCKX2 specifically interacted with the WD-40 repeats, a putative cargo-binding domain, of KIF21A...
March 21, 2012: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Gabriel Mercado Besserer, Debora A Nicoll, Jeff Abramson, Kenneth D Philipson
The superfamily of cation/Ca(2+) exchangers includes both Na(+)/Ca(2+) exchangers (NCXs) and Na(+)/Ca(2+),K(+) exchangers (NCKX) as the families characterized in most detail. These Ca(2+) transporters have prominent physiological roles. For example, NCX and NCKX are important in regulation of cardiac contractility and visual processes, respectively. The superfamily also has a large number of members of the YrbG family expressed in prokaryotes. However, no members of this family have been functionally expressed, and their transport properties are unknown...
March 9, 2012: Journal of Biological Chemistry
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