Sodium/(calcium + potassium) exchanger NCKX4 optimizes KLK4 activity in the enamel matrix microenvironment to regulate ECM modeling.

Enamel development is a process in which extracellular matrix models from a soft proteinaceous matrix to the most mineralized tissue in vertebrates. Patients with mutant , a gene encoding a K-dependent Na/Ca-exchanger, develop a hypomineralized and hypomature enamel. How NCKX4 regulates enamel protein removal to achieve an almost protein-free enamel is unknown.

Regulation of K-Dependent Na/Ca-Exchangers (NCKX).

Potassium-dependent sodium-calcium exchangers (NCKX) have emerged as key determinants of calcium (Ca) signaling and homeostasis, especially in environments where ion concentrations undergo large changes, such as excitatory cells and transport epithelia. The regulation of NCKX transporters enables them to respond to the changing cellular environment thereby helping to shape the extent and kinetics of Ca signals. This review examines the current knowledge of the different ways in which NCKX activity can be modulated.

Calmodulin binds and modulates K-dependent Na/Ca-exchanger isoform 4, NCKX4.

The family of K-dependent Na/Ca-exchangers, NCKX, are important mediators of cellular Ca 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.

Signal pathway analysis of selected obesity-associated melanocortin-4 receptor class V mutants.

Mutations in the melanocortin-4 receptor (MC4R) in humans are the single most common cause of rare monogenic 1severe obesity, and polymorphisms in this gene are also associated with obesity in the general population. The MC4R is a G-protein coupled receptor, and in vitro analysis suggests that MC4R can signal through several different G-protein subtypes. In vivo studies show complex outcomes, with different G-proteins in different cells responsible for different physiological responses linked to obesity.

Potassium-dependent sodium-calcium exchanger (NCKX) isoforms and neuronal function.

K-dependent Na/Ca-exchangers (NCKX) are a relatively recently described five-member gene family of transporters which play a quantitatively significant role in neuronal Ca transport. In this review we highlight the important individual contributions these transporters make to cellular Ca homeostasis and neuronal function. Notably, different members of the family make distinct, non-redundant, contributions to critical behavioural pathways.

Ambivalence: A Key to Clinical Trial Participation?

Trust exerts a multidimensional influence at the interpersonal level in the clinical trials setting. Trust and distrust are dynamic states that are impacted, either positively or negatively, with each participant-clinical trials team interaction. Currently, accepted models of trust posit that trust and distrust coexist and their effects on engagement and retention in clinical trials are mediated by ambivalence.

Building trust and diversity in patient-centered oncology clinical trials: An integrated model.

Background/aims: Trust is the cornerstone of clinical trial recruitment and retention. Efforts to decrease barriers and increase clinical trial participation among diverse populations have yielded modest results. There is an urgent need to better understand the complex interactions between trust and clinical trial participation.

Reduced Protein Expression of the Na/Ca+K-Exchanger (SLC24A4) in Apical Plasma Membranes of Maturation Ameloblasts of Fluorotic Mice.

Exposure of forming enamel to fluoride results into formation of hypomineralized enamel. We tested whether enamel hypomineralization was caused by lower expression of the NCKX4/SLC24A4 Ca-transporter by ameloblasts. Three commercial antibodies against NCKX4 were tested on enamel organs of wild-type and Nckx4-null mice, one of which (a mouse monoclonal) was specific.

Anatomical evidence for a non-synaptic influence of the K+ -dependent Na+/Ca2+ -exchanger, NCKX2, on hippocampal plasticity.

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.

An essential role for the K+-dependent Na+/Ca2+-exchanger, NCKX4, in melanocortin-4-receptor-dependent satiety.

K(+)-dependent Na(+)/Ca(2+)-exchangers are broadly expressed in various tissues, and particularly enriched in neurons of the brain. The distinct physiological roles for the different members of this Ca(2+) transporter family are, however, not well described. Here we show that gene-targeted mice lacking the K(+)-dependent Na(+)/Ca(2+)-exchanger, NCKX4 (gene slc24a4 or Nckx4), display a remarkable anorexia with severe hypophagia and weight loss.

Purinergic stimulation of K+-dependent Na+/Ca2+ exchanger isoform 4 requires dual activation by PKC and CaMKII.

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.

KIF21A-mediated axonal transport and selective endocytosis underlie the polarized targeting of NCKX2.

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).

Determination of apparent calcium affinity for endogenously expressed human sarco(endo)plasmic reticulum calcium-ATPase isoform SERCA3.

The sarco(endo)plasmic reticulum Ca(2+)-ATPases (SERCAs) play a crucial role in regulating free cytosolic Ca(2+) concentration in diverse cell types. It has been shown that recombinant SERCA3, when measured in heterologous systems, exhibits low apparent affinity for Ca(2+); however, Ca(2+) affinity of native SERCA3 in an endogenous setting has not been examined. Such a measurement is complicated, because SERCA3 is always coexpressed with the housekeeping isoform SERCA2b.

A critical role for the potassium-dependent sodium-calcium exchanger NCKX2 in protection against focal ischemic brain damage.

The superfamily of cation/Ca2+ plasma-membrane exchangers contains two branches, the K+-independent Na+-Ca2+ exchangers (NCXs) and the K+-dependent Na+-Ca2+ exchangers (NCKXs), widely expressed in mammals. NCKX2 is the major neuronally expressed isoform among NCKX members. Despite its importance in maintaining Na+, Ca2+, and K+ 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.

Na+/Ca2+ exchangers: three mammalian gene families control Ca2+ transport.

Mammalian Na+/Ca2+ exchangers are members of three branches of a much larger family of transport proteins [the CaCA (Ca2+/cation antiporter) superfamily] whose main role is to provide control of Ca2+ flux across the plasma membranes or intracellular compartments. Since cytosolic levels of Ca2+ are much lower than those found extracellularly or in sequestered stores, the major function of Na+/Ca2+ exchangers is to extrude Ca2+ from the cytoplasm. The exchangers are, however, fully reversible and thus, under special conditions of subcellular localization and compartmentalized ion gradients, Na+/Ca2+ exchangers may allow Ca2+ entry and may play more specialized roles in Ca2+ movement between compartments.

K+ -dependent Na+/Ca2+ exchangers: key contributors to Ca2+ signaling.

An elevation in cytosolic Ca2+ is a universal signaling mechanism that controls a vast array of physiological processes. K+ -dependent Na+/Ca2+ exchangers are a newly identified family of Ca2+ efflux transporters that play important and diverse roles in cellular Ca2+ homeostasis.

Involvement of the potassium-dependent sodium/calcium exchanger gene product NCKX2 in the brain insult induced by permanent focal cerebral ischemia.

Sodium/calcium exchangers are neuronal plasma membrane transporters, which by coupling Ca2+ and Na+ fluxes, may play a relevant role in brain ischemia. The exchanger gene superfamily comprises two arms: the K+-independent (NCX) and K+-dependent (NCKX) exchangers. In the brain, three different NCX (NCX1, NCX2, NCX3) and three NCKX (NCKX2, NCKX3, NCKX4) family members have been described.

Exchangers NCKX2, NCKX3, and NCKX4: identification of Thr-551 as a key residue in defining the apparent K(+) affinity of NCKX2.

K(+)-dependent Na(+)/Ca(2+) exchangers (NCKX) catalyze cytosolic Ca(2+) extrusion and are particularly important for neuronal Ca(2+) signaling. Of the five mammalian isoforms, the detailed functional characteristics have only been reported for NCKX1 and -2. In the current study, the functional characteristics of recombinant NCKX3 and -4 expressed in HEK293 cells were determined and compared with those of NCKX2.

Protein kinase C-dependent enhancement of activity of rat brain NCKX2 heterologously expressed in HEK293 cells.

Different members of the Na+/Ca2++K+ exchanger (NCKX) family are present in distinct brain regions, suggesting that they may have cell-specific functions. Many neuronal channels and transporters are regulated via phosphorylation. Regulation of the rat brain NCKXs by protein kinases, however, has not been described.

Metabolic regulation of sodium-calcium exchange by intracellular acyl CoAs.

The sodium-calcium exchanger (NCX) is a critical mediator of calcium homeostasis. In the heart, NCX1 predominantly operates in forward mode to extrude Ca(2+); however, reverse-mode NCX1 activity during ischemia/reperfusion (IR) contributes to Ca(2+) loading and electrical and contractile dysfunction. IR injury has also been associated with altered fat metabolism and accumulation of long-chain acyl CoA esters.

Novel role for K+-dependent Na+/Ca2+ exchangers in regulation of cytoplasmic free Ca2+ and contractility in arterial smooth muscle.

Cytoplasmic free Ca2+ ([Ca2+]cyt) is essential for the contraction and relaxation of blood vessels. The role of plasma membrane Na+/Ca2+ exchange (NCX) activity in the regulation of vascular Ca2+ homeostasis was previously ascribed to the NCX1 protein. However, recent studies suggest that a relatively newly discovered K+-dependent Na+/Ca2+ exchanger, NCKX (gene family SLC24), is also present in vascular smooth muscle.

Importance of K+-dependent Na+/Ca2+-exchanger 2, NCKX2, in motor learning and memory.

Plasma membrane Na+/Ca2+-exchangers play a predominant role in Ca2+ extrusion in brain. Neurons express several different Na+/Ca2+-exchangers belonging to both the K+-independent NCX family and the K+-dependent NCKX family. The unique contributions of each of these proteins to neuronal Ca2+ homeostasis and/or physiology remain largely unexplored.

Enrichment of endoplasmic reticulum with cholesterol inhibits sarcoplasmic-endoplasmic reticulum calcium ATPase-2b activity in parallel with increased order of membrane lipids: implications for depletion of endoplasmic reticulum calcium stores and apoptosis in cholesterol-loaded macrophages.

Macrophages in advanced atherosclerotic lesions accumulate large amounts of unesterified, or "free," cholesterol (FC). FC accumulation induces macrophage apoptosis, which likely contributes to plaque destabilization. Apoptosis is triggered by the enrichment of the endoplasmic reticulum (ER) with FC, resulting in depletion of ER calcium stores, and induction of the unfolded protein response.

Differential contribution of plasmalemmal Na/Ca exchange isoforms to sodium-dependent calcium influx and NMDA excitotoxicity in depolarized neurons.

Inhibition of Na(+),K(+)-ATPase during NMDA applications greatly increased NMDA-induced excitotoxicity in primary cultures of forebrain neurons (FNs), but not in cerebellar granule cells (CGCs). Because Na(+),K(+)-ATPase inhibition promotes reversal of plasmalemmal Na(+)/Ca(2+) exchangers, we compared the activities of reversed K(+)-independent (NCX) and K(+)-dependent (NCKX) Na(+)/Ca(2+) exchangers in these cultures. To this end, we measured gramicidin-induced and Na(+)-dependent elevation in cytosolic [Ca(2+)] ([Ca(2+)](c)) that represents Ca(2+) influx via reversed NCX and NCKX; NCX activity was dissected out by removing external K(+).