Ward S (1973) Proc Natl Acad Sci U S A "Chemotaxis by the nematode Caenorhabditis elegans: identification of attractants and analysis of the response by use of mutants."

Ward S

[Proc Natl Acad Sci U S A, 1973]

The nematode Caenorhabditis elegans is attracted by at least four classes of attractants: by cyclic nucleotides, cAMP and cGMP; by anions, Cl-, Br-, I-; by cations, Na+, Li+, K+, Mg+; and by alkaline pH values. The nematode's behavioral response to gradients of these attractants involves orientation and movement up the gradient, accumulation, and then habituation. Comparison of the tracks of wild-type and mutant animals responding to gradients of attractants indicates that sensory receptors in the head alone mediate the orientation response and that the direction of orientation is determined by the lateral motion of the head. Therefore, the orientation response is

Gopal E et al. (2015) J Pharmacol Exp Ther "Species-specific influence of lithium on the activity of SLC13A5 (NaCT): lithium-induced activation is specific for the transporter in primates."

Ganapathy V, Ramachandran S, Gopal E, Babu E, Prasad PD, Bhutia YD

[J Pharmacol Exp Ther, 2015]

NaCT (SLC13A5) is a Na(+)-coupled transporter for Krebs cycle intermediates and is expressed predominantly in the liver. Human NaCT is relatively specific for citrate compared with other Krebs cycle intermediates. The transport activity of human NaCT is stimulated by Li(+), whereas that of rat NaCT is inhibited by Li(+). We studied the influence of Li(+) on NaCTs cloned from eight different species. Li(+) stimulated the activity of only NaCTs from primates (human, chimpanzee, and monkey); by contrast, NaCTs from nonprimate species (mouse, rat, dog, and zebrafish) were inhibited by Li(+). Caenorhabditis elegans NaCT was not affected by Li(+). With human NaCT, the Li(+)-induced increase in transport activity was associated with the conversion of the transporter from a low-affinity/high-capacity type to a high-affinity/low-capacity type. H(+) was able to substitute for Li(+) in eliciting the stimulatory effect. The amino acid Phe500 in human NaCT was critical for Li(+)/H(+)-induced stimulation. Mutation of this amino acid to tryptophan (F500W) markedly increased the basal transport activity of human NaCT in the absence of Li(+), but the ability of Li(+) to stimulate the transporter was almost completely lost with this mutant. Substitution of Phe500 with tryptophan in human NaCT converted the transporter from a low-affinity/high-capacity type to a high-affinity/low-capacity type, an effect similar to that of Li(+) on the wild-type NaCT. These studies show that Li(+)-induced activation of NaCT is specific for the transporter in primates and that the region surrounding Phe500 in primate NaCTs is important for the Li(+) effect.

Palty R et al. (2004) J Biol Chem "Lithium-calcium exchange is mediated by a distinct potassium-independent sodium-calcium exchanger."

Ohana E, Argaman M, Palty R, Beharier O, Silverman WF, Hershfinkel M, Elgazar V, Volokita M, Sekler I

[J Biol Chem, 2004]

Sodium-calcium exchangers have long been considered inert with respect to monovalent cations such as lithium, choline, and N-methyl-d-glucamine. A key question that has remained unsolved is how despite this, Li(+) catalyzes calcium exchange in mammalian tissues. Here we report that a Na(+)/Ca(2+) exchanger, NCLX cloned from human cells (known as FLJ22233), is distinct from both known forms of the exchanger, NCX and NCKX in structure and kinetics. Surprisingly, NCLX catalyzes active Li(+)/Ca(2+) exchange, thereby explaining the exchange of these ions in mammalian tissues. The NCLX protein, detected as both 70- and 55-KDa polypeptides, is highly expressed in rat pancreas, skeletal muscle, and stomach. We demonstrate, moreover, that NCLX is a K(+)-independent exchanger that catalyzes Ca(2+) flux at a rate comparable with NCX1 but without promoting Na(+)/Ba(2+) exchange. The activity of NCLX is strongly inhibited by zinc, although it does not transport this cation. NCLX activity is only partially inhibited by the NCX inhibitor, KB-R7943. Our results provide a cogent explanation for a fundamental question. How can Li(+) promote Ca(2+) exchange whereas the known exchangers are inert to Li(+) ions? Identification of this novel member of the Na(+)/Ca(2+) superfamily, with distinct characteristics, including the ability to transport Li(+), may provide an explanation for this phenomenon.

Zou J et al. (2023) Nat Biotechnol "A DNA nanodevice for mapping sodium at single-organelle resolution."

Gupta PD, Mitra K, Smith JJ, Rao R, Ramirez JR, Zou J, Anees P, Krishnan Y, Oettinger D, Veetil AT, Kratsios P

[Nat Biotechnol, 2023]

Cellular sodium ion (Na⁺) homeostasis is integral to organism physiology. Our current understanding of Na⁺ homeostasis is largely limited to Na⁺ transport at the plasma membrane. Organelles may also contribute to Na⁺ homeostasis; however, the direction of Na⁺ flow across organelle membranes is unknown because organellar Na⁺ cannot be imaged. Here we report a pH-independent, organelle-targetable, ratiometric probe that reports lumenal Na⁺. It is a DNA nanodevice containing a Na⁺-sensitive fluorophore, a reference dye and an organelle-targeting domain. By measuring Na⁺ at single endosome resolution in mammalian cells and Caenorhabditis elegans, we discovered that lumenal Na⁺ levels in each stage of the endolysosomal pathway exceed cytosolic levels and decrease as endosomes mature. Further, we find that lysosomal Na⁺ levels in nematodes are modulated by the Na⁺/H⁺ exchanger NHX-5 in response to salt stress. The ability to image subcellular Na⁺ will unveil mechanisms of Na⁺ homeostasis at an increased level of cellular detail.

Inokuchi A et al. (2015) J Appl Toxicol "Effects of lithium on growth, maturation, reproduction and gene expression in the nematode Caenorhabditis elegans."

Matsusaki H, Yamamoto R, Takumi S, Morita F, Inokuchi A, Arizono K, Tominaga N, Ishibashi H

[J Appl Toxicol, 2015]

Lithium (Li) has been widely used to treat bipolar disorder, and industrial use of Li has been increasing; thus, environmental pollution and ecological impacts of Li have become a concern. This study was conducted to clarify the potential biological effects of LiCl and Li(2)CO(3) on a nematode, Caenorhabditis elegans as a model system for evaluating soil contaminated with Li. Exposure of C. elegans to LiCl and Li(2)CO(3) decreased growth/maturation and reproduction. The lowest observed effect concentrations for growth, maturation and reproduction were 1250, 313 and 10 000m, respectively, for LiCl and 750, 750 and 3000m, respectively, for Li(2)CO(3). We also investigated the physiological function of LiCl and LiCO(3) in C. elegans using DNA microarray analysis as an eco-toxicogenomic approach. Among approximately 300 unique genes, including metabolic genes, the exposure to 78m LiCl downregulated the expression of 36 cytochrome P450, 16 ABC transporter, 10 glutathione S-transferase, 16 lipid metabolism and two vitellogenin genes. On the other hand, exposure to 375m Li(2)CO(3) downregulated the expression of 11 cytochrome P450, 13 ABC transporter, 13 lipid metabolism and one vitellogenin genes. No gene was upregulated by LiCl or Li(2)CO(3). These results suggest that LiCl and Li(2)CO(3) potentially affect the biological and physiological function in C. elegans associated with alteration of the gene expression such as metabolic genes. Our data also provide experimental support for the utility of toxicogenomics by integrating gene expression profiling into a toxicological study of an environmentally important organism such as C. elegans.

McColl G et al. (2008) J Biol Chem "Pharmacogenetic analysis of lithium-induced delayed aging in Caenorhabditis elegans."

Melov S, McColl G, Lithgow GJ, Vantipalli MC, Killilea DW, Hubbard AE

[J Biol Chem, 2008]

Lithium (Li+) has been used to treat mood affect disorders, including bipolar, for decades (1;2). This drug is neuroprotective and has several identified molecular targets. However, it has a narrow therapeutic range and the underlying mechanism(s) of its therapeutic action is not understood. Here we describe a pharmacogenetic study of Li+ in the nematode Caenorhabditis elegans. Exposure to Li+ at clinically relevant concentrations throughout adulthood increases survival during normal aging (up to 46% median increase). Longevity is extended via a novel mechanism with altered expression of genes encoding nucleosome-associated functions. Li+ treatment results in reduced expression of the worm ortholog of LSD-1 (T08D10.2), a histone demethylase; knockdown by RNA interference (RNAi) of T08D10.2 is sufficient to extend longevity (~25% median increase), suggesting Li+ regulates survival by modulating histone methylation and chromatin structure.

Yuan A et al. (2003) Neuron "The sodium-activated potassium channel is encoded by a member of the Slo gene family."

Yuan A, Santi CM, Pollak K, Kaczmarek L, Crowder CM, Wang ZW, Wei A, Nonet M, Salkoff L

[Neuron, 2003]

Na+-activated potassium channels (K-Na) have been identified in cardiomyocytes and neurons where they may provide protection against ischemia. We now report that K-Na is encoded by the rSlo2 gene (also called Slack), the mammalian ortholog of slo-2 in C. elegans. rSlo2, heterologously expressed, shares many properties of native K-Na including activation by intracellular Na+, high conductance, and prominent subconductance states. In addition to activation by Na+, we report that rSLO-2 channels are cooperatively activated by intracellular Cl-, similar to C. elegans SLO-2 channels. Since intracellular Na+ and Cl- both rise in oxygen-deprived cells, coactivation may more effectively trigger the activity of rSLO-2 channels in ischemia. In C. elegans, mutational and physiological analysis revealed that the SLO-2 current is a major component of the delayed rectifier. We demonstrate in C. elegans that slo-2 mutants are hypersensitive to hypoxia, suggesting a conserved role for the slo-2 gene

Wang L et al. (2017) J Neurosci "A Gustatory Neural Circuit of Caenorhabditis elegans Generates Memory-Dependent Behaviors in Na+ Chemotaxis."

Wang L, Sato H, Kunitomo H, Tomioka M, Satoh Y, Iino Y

[J Neurosci, 2017]

Animals show various behaviors in response to environmental chemicals. These behaviors are often plastic depending on previous experiences. Caenorhabditis elegans, which has highly developed chemosensory system with a limited number of sensory neurons, is an ideal model for analyzing the role of each neuron in innate and learned behaviors. Here we report a new type of memory-dependent behavioral plasticity in Na(+) chemotaxis generated by the left member of bilateral gustatory neuron pair ASE (ASEL neuron). When worms were cultivated in the presence of Na(+), they showed positive chemotaxis towards Na(+); but when worms were cultivated under Na(+)-free conditions, they showed no preference in Na(+) concentration. Both channelrhodopsin-2 (ChR2) activation with blue light and upsteps of Na(+) concentration activated ASEL only after cultivation with Na(+), as judged by increase in intracellular Ca(2+) Under cultivation conditions with Na(+), photoactivation of ASEL caused activation of its downstream interneurons AIY and AIA, which stimulate forward locomotion, and inhibition of its downstream interneuron AIB, which inhibits the turning/reversal behavior, and overall drove worms towards higher Na(+) concentrations. We also found that the Gq signaling pathway and the neurotransmitter glutamate are both involved in the behavioral response generated by ASEL. SIGNIFICANCE STATEMENT: Animals have acquired various types of behavioral plasticity during their long evolutionary history. C. elegans prefers odors associated with food, but plastically changes its behavioral response according to previous experience. Here we report a new type of behavioral response generated by a single gustatory sensory neuron, the ASE-left neuron (ASEL). ASEL did not respond to photostimulation or upsteps of Na(+) concentration when worms were cultivated in Na(+)-free conditions; however, when worms were cultivated with Na(+), ASEL responded and inhibited AIB to avoid turning, and stimulated AIY and AIA to promote forward locomotion, which collectively drove worms towards higher Na(+) concentrations. Glutamate and the Gq signaling pathway are essential for driving worms towards higher Na(+) concentrations.

Johnson CK et al. (2020) J Neurophysiol "The Na+/K+-ATPase is needed in glia of touch receptors for responses to touch in C. elegans."

Wang Y, Bianchi L, Fernandez-Abascal J, Johnson CK, Wang L

[J Neurophysiol, 2020]

Four of the five types of mammalian mechanosensors are composed of nerve endings and accessory cells. In C. elegans we showed that glia supports the function of nose touch neurons via the activity of glial Na⁺ and K⁺channels. We show here that a third regulator of Na⁺ and K⁺, the Na⁺/K⁺-ATPase, is needed in glia of nose touch neurons for touch. Importantly, we show that the two Na⁺/K⁺-ATPase genes are needed for the function rather than structural integrity and that their ion transport activity is crucial for touch. Finally, when glial Na⁺/K⁺-ATPase genes are knocked-out, touch can be restored by activation of a third Na⁺/K⁺-ATPase. Taken together, these data show the requirement in glia of touch neurons of the function of the Na⁺/K⁺-ATPase. These data underscore the importance of the homeostasis of Na⁺ and K⁺, most likely in the space surrounding touch neurons, in touch sensation, a function that might be conserved across species.

Bruckbauer A et al. (2017) Am J Cardiovasc Dis "Leucine-nicotinic acid synergy stimulates AMPK/Sirt1 signaling and regulates lipid metabolism and lifespan in Caenorhabditis elegans, and hyperlipidemia and atherosclerosis in mice."

Zemel MB, Li F, Cao Q, Cui X, Bruckbauer A, Zha L, Jing J, Xue B, Banerjee J, Shi H

[Am J Cardiovasc Dis, 2017]

BACKGROUND/AIMS: Nicotinic acid (NA), a lipid-lowering drug, serves as a source of NAD(+), the cofactor for Sirt1. Leucine (Leu) stimulates the AMPK/Sirt1 axis and amplifies the effects of other AMPK/Sirt1 activating compounds. Therefore, we tested the interactive effects of leucine and low dose NA on AMPK/Sirt1 signaling and downstream effects of lipid metabolism in cell culture, C. elegans and mice. METHODS: LDL-receptor knockout mice were fed an atherogenic Western diet supplemented with leucine (24 g/kg diet) and sub-therapeutic NA combinations (50 mg/kg diet and 250 mg/kg diet) or low therapeutic NA (1000 mg/kg diet) for 8 weeks to evaluate markers of hyperlipidemia and atherosclerosis. RESULTS: NA-Leu increased P-AMPK and Sirt1 in adipocytes and myotubes. In C. elegans, NA-Leu increased P-AMPK and DAF-16 (FOXO), reduced lipid accumulation and increased median survival under mild oxidative stress conditions. In the mice, NA-Leu reduced total cholesterol, cholesterol esters, plasma triglycerides, atherosclerotic lesion size, lipid area, and aortic macrophage infiltration, similar to the therapeutic NA dose. CONCLUSION: Leu amplifies the effects of NA on lipid metabolism, hyperlipidemia and atherosclerosis in mice, at least in part by activation of the AMPK/Sirt1 axis. This combination may be a potential therapeutic alternative for hyperlipidemia and atherosclerosis.