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.

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.

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.

Sun Y et al. (2024) J Cell Biol "A RAB transition orchestrates membrane trafficking in unconventional protein secretion."

Sun Y, Ge L, Zhang M

[J Cell Biol, 2024]

Rab GTPases function as intracellular molecular switches that regulate vesicular transport. In the current issue, Li et al. (https://doi.org/10.1083/jcb.202306107) revealed RAB-8 to RAB-11 transition governing the unconventional secretion of membrane proteins in the intestinal epithelium of C. elegans.

White RA et al. (2000) Cytogenet Cell Genet "The gene encoding TBC1D1 with homology to the tre-2/USP6 oncogene, BUB2, and cdc16 maps to mouse chromosome 5 and human chromosome 4."

Zon LI, White RA, Pasztor LM, Richardson PM

[Cytogenet Cell Genet, 2000]

TBC1D1 is the founding member of a family of related proteins with homology to tre-2/UPS6, BUB2, and cdc16 and containing the tbc box motif of 180-220 amino acids. This protein family is thought to have a role in differentiation and in regulating cell growth. We set out to map the TBC1D1 gene in mouse and human. Segregation analysis of a TBC1D1 RFLP in two independent mouse RI (recombinant inbred) lines reveals that mouse Tbc1d1 is closely linked to Pgm1 on chromosome 5. The human TBC1D1 gene was assigned to human chromosome 4p15.1-->4q21 using Southern blot analyses of genomic DNAs from rodent-human somatic cell lines. A human-specific genomic fragment was observed in the somatic cell lines containing human chromosome 4 or the 4p15.1-->4q21 region of the chromosome. TBC1D1 maps to the region containing the ortholog of mouse Pgm1 adding another locus to this long region of conserved synteny between mouse and man.

Li T et al. (2022) STAR Protoc "Live imaging of postembryonic developmental processes in C.elegans."

Wang X, Zou Y, Li T, Feng Z

[STAR Protoc, 2022]

Live imaging is an important tool to track dynamic processes such as neuronal patterning events. Here, we describe a protocol for time-lapse microscopy analysis using neuronal migration and dendritic growth as examples. This protocol can provide detailed information for understanding cellular dynamics during postembryonic development in Caenorhabditis elegans (C. elegans). For complete details on the use and execution of this protocol, please refer to Feng etal. (2020), Li etal. (2021), and Wang etal. (2021).

Macdonald BA et al. (2006) Blood "Zebrafish to humans: evolution of the alpha3-chain of type IV collagen and emergence of the autoimmune epitopes associated with Goodpasture syndrome."

Kalluri R, Sund M, Zon LI, Pfaff KL, Holthaus K, Macdonald BA, Grant MA

[Blood, 2006]

Goodpasture''s syndrome is an autoimmune vascular disease associated with kidney and lung failure, with pathogenic circulating autoantibodies targeted to a set of discontinuous epitope sequences within the non-collagenous domain-1 (NC1) of the alpha3 chain of type IV collagen [alpha3(IV)NC1], the Goodpasture''s autoantigen. We demonstrate that basement membrane extracted NC1 domain preparations from C. elegans, Drosophila melanogaster and Danio rerio do not bind Goodpasture''s autoantibodies, while Xenopus laevis, chicken, mouse and human alpha3(IV)NC1 domains bind autoantibodies. The alpha3(IV)-chain is not present in C. elegans and Drosophila melanogaster, but is first detected in the Danio rerio. Interestingly, native Danio rerio alpha3(IV)NC1 does not bind Goodpasture''s autoantibodies. Next, we cloned, sequenced and generated recombinant Danio rerio alpha3(IV)NC1 domain. In contrast to recombinant human alpha3(IV)NC1 domain, there was complete absence of autoantibody binding to recombinant Danio rerio alpha3(IV)NC1. 3D molecular modeling from existing x-ray co-ordinates of human NC1 domain suggest that evolutionary alteration of electrostatic charge and polarity due to the emergence of critical serine, aspartic acid and lysine residues, accompanied by the loss of asparagine and glutamine contributes to the emergence of the two major Goodpasture''s epitopes on the human alpha3(IV)NC1 domain, as it evolved from the Danio rerio over 450 million years.

Waldmann R et al. (1996) J Biol Chem "The mammalian degenerin MDEG, an amiloride-sensitive cation channel activated by mutations causing neurodegeneration in Caenorhabditis elegans."

Waldmann R, Champigny G, Lazdunski M, Lauritzen I, Voilley N

[J Biol Chem, 1996]

Mutations of the degenerins (deg-1, mec-4, mec-10) are the major known causes of hereditary neurodegeneration in the nematode Caenorhabditis elegans. We cloned a neuronal degenerin (MDEG) from human and rat brain. MDEG is an amiloride-sensitive cation channel permeable for Na+, K+, and Li+. This channel is activated by the same mutations which cause neurodegeneration in C. elegans. Like the hyperactive C. elegans degenerin mutants, constitutively active mutants of MDEG cause cell death, suggesting that gain of function of this novel neuronal ion channel might be involved in human forms of neurodegeneration.

Liu H et al. (2021) STAR Protoc "Protocols for electrophysiological recordings and electron microscopy at C.elegans neuromuscular junction."

Richmond JE, Krout M, Chen J, Sheoran S, Liu H, Hu Z, Li L, Zhao Q

[STAR Protoc, 2021]

Release of neurotransmitters by synaptic vesicle exocytosis at presynaptic terminals is critical for neuronal communication within the nervous system. Electrophysiology and electron microscopy are powerful and complementary approaches used to evaluate the function of synaptic proteins in synaptic transmission. Here, we provide a protocol detailing the use of these two approaches at C.elegans neuromuscular junctions, including steps for worm picking and dissection, in vivo electrophysiological recording, and sample preparation for electron microscopy, followed by imaging and analysis. For complete details on the use and execution of this protocol, please refer to Liu etal. (2021) and Li etal. (2021).