NCKX family

Calcium (Ca2+) extrusion is an essential function of the enamel-forming ameloblasts, providing Ca2+ for extracellular mineralization. The plasma membrane Ca2+ ATPases (PMCAs) remove cytosolic Ca2+ (cCa2+) and were recently shown to be efficient when ameloblasts experienced low cCa2+ elevation. Sodium-calcium (Na+/Ca2+) exchange has higher capacity to extrude cCa2+, but there is limited evidence on the function of the two main families of Na+/Ca2+ exchangers in enamel formation. The purpose of this study was to analyze the function of the NCX (coded by SLC8) and the K+-dependent NCKX (coded by SLC24) exchangers in rat ameloblasts and to compare their efficacy in the two main stages of enamel formation: the enamel forming secretory stage and the mineralizing or maturation stage...

Calcium signaling is ubiquitous in nematode development from fertilization to cell specification to apoptosis. Calcium also regulates dauer entry in Caenorhabditis elegans, which corresponds to the infective stage of parasitic nematodes. In diverse parasites such as Trypanosoma cruzi and Toxoplasma gondii calcium has been shown to regulate host cell entry and egress, and perturbing calcium signaling represents a possible route to inhibit infection and parasitism in these species. Sodium calcium exchangers are considered the most important mechanism of calcium efflux, and our lab has previously characterized the sodium calcium exchanger gene family in C...

The family of K+ -dependent Na+ /Ca2+ -exchangers, NCKX, are important mediators of cellular Ca2+ efflux, particularly in neurons associated with sensory transduction. The NCKX family comprises five proteins, NCKX1-5, each being the product of a different SLC24 gene. NCKX4 (SLC24A4) has been found to have a critical role in termination and adaptation of visual and olfactory signals, melanocortin-dependent satiety signaling, and the maturation of dental enamel. To explore mechanisms that might influence the temporal control of NCKX4 activity, a yeast two-hybrid system was used to search for protein interaction partners...

The family of K+-dependent Na+/Ca2+-exchangers, NCKX, are important mediators of cellular Ca2+ efflux, particularly in neurons associated with sensory transduction. The NCKX family comprises five proteins, NCKX1-5, each the product of a different SLC24 gene. NCKX4 ( SLC24A4 ) has been found to have a critical role in termination and adaptation of visual and olfactory signals, melanocortin-dependent satiety signaling, and the maturation of dental enamel. To explore mechanisms that might influence the temporal control of NCKX4 activity, a yeast two-hybrid system was used to search for protein interaction partners...

K+ -dependent Na+ /Ca2+ exchanger proteins (NCKX1-5) of the SLC24 gene family play important roles in a wide range of biological processes including but not limited to rod and cone photoreceptor vision, olfaction, enamel formation and skin pigmentation. NCKX proteins are also widely expressed throughout the brain and NCKX2 and NCKX4 knockouts in mice have specific phenotypes. Here we review our work on structure-function relationships of NCKX proteins. We discuss membrane topology, domains critical to transport function, and residues critical to cation binding and transport function, all in the context of crystal structures that were obtained for the archaeal Na+ /Ca2+ exchanger NCX_Mj...

K+ -dependent Na+ /Ca2+ -exchangers (NCKX) are a relatively recently described five-member gene family of transporters which play a quantitatively significant role in neuronal Ca2+ transport. In this review we highlight the important individual contributions these transporters make to cellular Ca2+ homeostasis and neuronal function. Notably, different members of the family make distinct, non-redundant, contributions to critical behavioural pathways. In particular, NCKX proteins regulate the kinetics, termination and adaptation of Ca2+ signals in sensory transduction neurons in the olfactory and visual systems...

NCKX5 is a bidirectional K+ -dependent Na+ -Ca2+ exchanger, which belongs to the SLC24A gene family. In particular, the A111T mutation of NCKX5 has been associated with reduced pigmentation in European populations. In contrast to other NCKX isoforms, which function in the plasma membrane (PM), NCKX5 has been shown to localize either in the trans-Golgi network (TGN) or in melanosomes. Moreover, sequences responsible for retaining its intracellular localization are unknown. This study addresses two major questions: (i) clarification of intracellular location of NCKX5 and (ii) identification of sequences that retain NCKX5 inside the cell...

Loss of intracellular calcium homeostasis may contribute to the opacification of lens tissue during cortical cataract formation. In healthy lenses, the concentration of intracellular calcium is maintained at levels far below electrochemical equilibrium but the identity of the calcium extrusion mechanism in lens fiber cells has remained elusive. Previous studies focused on the role of plasma membrane calcium ATPases and sodium-calcium exchangers. Here, we examined the expression of mRNA transcripts encoding potassium-dependent sodium-calcium exchangers (Nckx's, encoded by the Slc24 gene family) in the mouse lens...

Among five members of the K+ -dependent Na+ /Ca2+ exchanger (NCKX) family (NCKX1-5), only NCKX2 is highly expressed in mouse brain. NCKX2 in plasma membranes mediates cytosolic calcium excretion through electrogenic exchange of 4 Na+ for 1 Ca2+ and 1 K+ . Here, we observed significantly decreased levels of NCKX2 protein and mRNA in the CA1 region of APP23 mice, a model of Alzheimer's disease. We also found that, like APP23 mice, heterozygous NCKX2-mutant mice exhibit mildly impaired hippocampal LTP and memory acquisition, the latter based on novel object recognition and passive avoidance tasks...

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...

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...

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...

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...

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...

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...

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...

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...

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...

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...

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...