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Physiol Rev,
1999]
The Na+/Ca2+ exchanger, an ion transport protein, is expressed in the plasma membrane (PM) of virtually all animal cells. It extrudes Ca2+ in parallel with the PM ATP-driven Ca2+ pump. As a reversible transporter, it also mediates Ca2+ entry in parallel with various ion channels. The energy for net Ca2+ transport by the Na+/Ca2+ exchanger and its direction depend on the Na+, Ca2+, and K+ gradients across the PM, the membrane potential, and the transport stoichiometry. In most cells, three Na+ are exchanged for one Ca2+. In vertebrate photoreceptors, some neurons, and certain other cells, K+ is transported in the same direction as Ca2+, with a coupling ratio of four Na+ to one Ca2+ plus one K+. The exchanger kinetics are affected by nontransported Ca2+, Na+, protons, ATP, and diverse other modulators. Five genes that code for the exchangers have been identified in mammals: three in the Na+/Ca2+ exchanger family (NCX1, NCX2, and NCX3) and two in the Na+/Ca2+ plus K+ family (NCKX1 and NCKX2). Genes homologous to NCX1 have been identified in frog, squid, lobster, and Drosophila. In mammals, alternatively spliced variants of NCX1 have been identified; dominant expression of these variants is cell type specific, which suggests that the variations are involved in targeting and/or functional differences. In cardiac myocytes, and probably other cell types, the exchanger serves a housekeeping role by maintaining a low intracellular Ca2+ concentration; its possible role in cardiac excitation-contraction coupling is controversial. Cellular increases in Na+ concentration lead to increases in Ca2+ concentration mediated by the Na+/Ca2+ exchanger; this is important in the therapeutic action of cardiotonic steroids like digitalis. Similarly, alterations of Na+ and Ca2+ apparently modulate basolateral K+ conductance in some epithelia, signaling in some special sense organs (e.g., photoreceptors and olfactory receptors) and Ca2+-dependent secretion in neurons and in many secretory cells. The juxtaposition of PM and sarco(endo)plasmic reticulum membranes may permit the PM Na+/Ca2+ exchanger to regulate sarco(endo)plasmic reticulum Ca2+ stores and influence cellular Ca2+ signaling.
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Annu Rev Physiol,
2000]
Plasma membrane Na(+)-Ca2+ exchange is an essential component of Ca2+ signaling pathways in several tissues. Activity is especially high in the heart where the exchanger is an important regulator of contractility. An expanding exchanger superfamily includes three mammalian Na(+)-Ca2+ exchanger genes and a number of alternative splicing products. New information indicates that the exchanger protein has nine transmembrane segments. The exchanger, which transports Na+ and Ca2+, is also regulated by these substrates. Some molecular information is available on regulation by Na+ and Ca2+ and by PIP2 and phosphorylation. Altered expression of the exchanger in pathophysiological states may contribute to various cardiac phenotypes. Use of transgenic approaches is beginning to improve our knowledge of exchanger function.
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Curr Opin Neurobiol,
1998]
Ion channels in the amiloride-sensitive Na+ channel/degenerin (NaC/DEG) family of cation channels have very diverse functions. They can be constitutively active (e.g. the epithelial Na+ channel), gated by a ligand (e.g. the peptide-gated channel FaNaC or H+-gated cation channels [ASICs]) or possibly activated by stretch (degenerins of Caenorhabditis elegans). Despite this functional diversity, the heterologous expressed channels share the following properties: permeability to Na+, inhibition by the diuretic amiloride and no voltage gating. This review will focus on recent advances in this ion channel family, with special emphasis on H+-gated cation channels.
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Biochem J,
2007]
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. The NCX (Na+/Ca2+ exchanger) [SLC (solute carrier) 8] branch of Na+/Ca2+ exchangers comprises three members: NCX1 has been most extensively studied, and is broadly expressed with particular abundance in heart, brain and kidney, NCX2 is expressed in brain, and NCX3 is expressed in brain and skeletal muscle. The NCX proteins subserve a variety of roles, depending upon the site of expression. These include cardiac excitation-contraction coupling, neuronal signalling and Ca2+ reabsorption in the kidney. The NCKX (Na2+/Ca2+-K+ exchanger) (SLC24) branch of Na+/Ca2+ exchangers transport K+ and Ca2+ in exchange for Na+, and comprises five members: NCKX1 is expressed in retinal rod photoreceptors, NCKX2 is expressed in cone photoreceptors and in neurons throughout the brain, NCKX3 and NCKX4 are abundant in brain, but have a broader tissue distribution, and NCKX5 is expressed in skin, retinal epithelium and brain. The NCKX proteins probably play a particularly prominent role in regulating Ca2+ flux in environments which experience wide and frequent fluctuations in Na+ concentration. Until recently, the range of functions that NCKX proteins play was generally underappreciated. This situation is now changing rapidly as evidence emerges for roles including photoreceptor adaptation, synaptic plasticity and skin pigmentation. The CCX (Ca2+/cation exchanger) branch has only one mammalian member, NCKX6 or NCLX (Na+/Ca2+-Li+ exchanger), whose physiological function remains unclear, despite a broad pattern of expression.
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Physiology (Bethesda),
2009]
Recent work shows that transport-independent as well as transport-dependent functions of ion transporters, and in particular the Na-K-ATPase, are required for formation and maintenance of several intercellular junctions. Furthermore, these junctional and other nonjunctional functions of ion transporters contribute to development of epithelial tubes. Here, we consider what has been learned about the roles of ion pumps in formation of junctions and epithelial tubes in mammals, zebrafish, Drosophila, and C. elegans. We propose that asymmetric association of the Na-K-ATPase with cell junctions early in metazoan evolution enabled vectorial transcellular ion transport and control of intraorganismal environment. Ion transport-independent functions of the Na-K-ATPase arose as junctional complexes evolved.
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[
Bioessays,
1999]
To the surprise of many, studies of molecular mechanisms of touch transduction and analyses of epithelial Na+ transport have converged to define a new class of ion channel subunits. Based on the names of the first two identified subfamilies, the Caenorhabditis elegans degenerins and the vertebrate epithelial amiloride-sensitive Na+ channel, this ion channel class is called the DEG/ENaC superfamily. Members of the DEG/ENaC superfamily have been found in nematodes, flies, snails, and vertebrates. Family members share common topology, such that they span the membrane twice and have intracellular N- and C-termini; a large extracellular loop includes a conserved cysteine-rich region. DEG/ENaC channels have been implicated a broad spectrum of cellular functions, including mechanosensation, proprioception, pain sensation, gametogenesis, and epithelial Na+ transport. These channels exhibit diverse gating properties, ranging from near constitutive opening to rapid inactivation. We discuss working understanding of DEG/ENaC functions, channel properties, structure/activity correlations and possible evolutionary relationship to other channel classes.
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Pflugers Arch,
2008]
The epithelial Na(+) channel (ENaC) is the rate-limiting step for Na(+) absorption in various vertebrate epithelia and deeply enmeshed in the control of salt and water homeostasis. The phylogenetic relationship of ENaC molecules to mechano-sensitive Degenerins from Caenorhabditis elegans indicates that ENaC might be mechano-sensitive as well. Primarily, it was suggested that ENaC might be activated by membrane stretch. However, this issue still remains to be clarified because controversial results were published. Recent publications indicate that shear stress represents an adequate stimulus, activating ENaC via increasing the single-channel open probability. Basing on the experimental evidence published within the past years and integrating this knowledge into a model related to the mechano-sensitive receptor complex known from C. elegans, we introduce a putative mechanism concerning the mechano-sensitivity of ENaC. We suggest that mechano-sensitive ENaC activation represents a nonhormonal regulatory mechanism. This feature could be of considerable physiological significance because many Na(+)-absorbing epithelia are exposed to shear forces. Furthermore, it may explain the wide distribution of ENaC proteins in nonepithelial tissues. Nevertheless, it remains a challenge for future studies to explore the mechanism how ENaC is controlled by mechanical forces and shear stress in particular.
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Genesis,
2014]
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. The Na(+) /Ca(2+) exchangers (NCX), Na(+) /Ca(2+) /K(+) exchangers (NCKX), and Ca(2+) /Cation exchangers (CCX) are the three classes of sodium calcium antiporters found in animals. These exchanger proteins utilize an electrochemical gradient to extrude calcium. Although they have been studied for decades, much is still unknown about these proteins. In this review, we examine current knowledge about the structure, function, and physiology and also discuss their implication in various developmental disorders. Finally, we highlight recent data characterizing the family of sodium calcium exchangers in the model system, Caenorhabditis elegans, and propose that C. elegans may be an ideal model to complement other systems and help fill gaps in our knowledge of sodium calcium exchange biology.
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Pflugers Arch,
2015]
Mechanosensory neurons, whose activity is controlled by mechanical force, underlie the senses of touch, hearing, and proprioception, yet despite their importance, the molecular basis of mechanotransduction is poorly understood. Genetic studies in Caenorhabditis elegans have provided a useful approach for identifying potential components of mechanotransduction complexes that might be conserved in more complex organisms. This review describes the mechanosensory systems of C. elegans, including the sensory neurons and circuitry involved in body touch, nose touch, and proprioception. In addition, the roles of genes encoding known and potential mechanosensory receptors, including members of the broadly conserved transient receptor potential (TRP) and degerin/epithelial Na(+) channel (DEG/ENaC) channel families, are discussed.
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Biochim Biophys Acta,
2010]
Precise regulation of the intracellular concentration of chloride [Cl-]i is necessary for proper cell volume regulation, transepithelial transport, and GABA neurotransmission. The Na-K-2Cl (NKCCs) and K-Cl (KCCs) cotransporters, related SLC12A transporters mediating cellular chloride influx and efflux, respectively, are key determinants of [Cl-]i in numerous cell types, including red blood cells, epithelial cells, and neurons. A common "chloride/volume-sensitive kinase", or related system of kinases, has long been hypothesized to mediate the reciprocal but coordinated phosphoregulation of the NKCCs and the KCCs, but the identity of these kinase(s) has remained unknown. Recent evidence suggests that the WNK (with no lysine = K) serine-threonine kinases directly or indirectly via the downstream Ste20-type kinases SPAK/OSR1, are critical components of this signaling pathway. Hypertonic stress (cell shrinkage), and possibly decreased [Cl-]i, triggers the phosphorylation and activation of specific WNKs, promoting NKCC activation and KCC inhibition via net transporter phosphorylation. Silencing WNK kinase activity can promote NKCC inhibition and KCC activation via net transporter dephosphorylation, revealing a dynamic ability of the WNKs to modulate [Cl-]. This pathway is essential for the defense of cell volume during osmotic perturbation, coordination of epithelial transport, and gating of sensory information in the peripheral system. Commiserate with their importance in serving these critical roles in humans, mutations in WNKs underlie two different Mendelian diseases, pseudohypoaldosteronism type II (an inherited form of salt-sensitive hypertension), and hereditary sensory and autonomic neuropathy type 2. WNKs also regulate ion transport in lower multicellular organisms, including Caenorhabditis elegans, suggesting that their functions are evolutionarily-conserved. An increased understanding of how the WNKs regulate the Na-K-2Cl and K-Cl cotransporters may provide novel opportunities for the selective modulation of these transporters, with ramifications for common human diseases like hypertension, sickle cell disease, neuropathic pain, and epilepsy.