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.

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.

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.

Buddell, Tyler et al. (2021) MicroPubl Biol

Quinn, Christopher C, Buddell, Tyler

[MicroPubl Biol, 2021]

The egl-19 gene in C. elegans encodes the pore forming subunit for the L-type voltage gated calcium channel that is homologous to the CACNA1C gene in humans (Lee et al., 1997). Variants in CACNA1C are risk factors for autism and other neurodevelopmental disorders (Li et al., 2015; Lu et al., 2012; Strom, et al., 2010). Timothy syndrome is a syndromic form of autism that can be caused by either of three rare de novo mutations in CACNA1C. These mutations cause either a G402R, G402S or G406R mutation in the CACNA1C protein (Splawski et al., 2004; Bader et al., 2011). Our previous work demonstrated that PLM axon termination is disrupted by mutations equivalent to the G402R and G406R mutations in CACNA1C (Buddell et al., 2019). Our study also revealed behavioral defects in these mutant worms. Although the anatomical basis for these behavioral defects has not been determined, it is likely that they are caused by multiple defects within the mechanosensory system.

Vo, An A. et al. (2021) MicroPubl Biol

Ward, Jordan D., Ragle, James Matthew, Levenson, Max T., Vo, An A.

[MicroPubl Biol, 2021]

The AID system has emerged as a powerful tool to conditionally deplete proteins in a wide-range of organisms and cell types (Nishimura et al. 2009; Holland et al. 2012; Zhang et al. 2015; Natsume et al. 2016; Trost et al. 2016; Brown et al. 2017; Daniel et al. 2018; Chen et al. 2018; Camlin and Evans 2019). The system is comprised of two components. A plant F-box protein Transport Inhibitor Response 1 (TIR1) is expressed and forms a complex with endogenous Skp1 and Cul1 proteins to form a functional SCF ubiquitin ligase (Nishimura et al. 2009; Natsume and Kanemaki 2017). TIR1 can either be expressed constitutively or in a tissue-specific manner depending on promoter choice. A degron sequence from the IAA17 protein is fused to the protein of interest (Nishimura et al. 2009; Natsume and Kanemaki 2017). Commonly used auxin-inducible degrons include 44 amino acid (AID*) and 68 amino acid (mAID) fragments of IAA17 (Morawska and Ulrich 2013; Li et al. 2019). Addition of the plant hormone auxin bridges an interaction between TIR1 and the degron and the SCF ligase ubiquitylates the degron-fused protein leading to proteasomal degradation.

Chamoli, Manish et al. (2020) MicroPubl Biol

Chinta, Shankar J, Andersen, Julie K, Lithgow, Gordon J, Chamoli, Manish

[MicroPubl Biol, 2020]

Kavain belongs to a group of lactone-based compounds collectively known as kavalactones, present in the pepper plant kava (P. methysticum). Kavalactones have been shown to possess diverse biological activities including sedation and anxiolysis (Ooi et al., 2018). Kavain in particular has been demonstrated to show potent anti-inflammatory properties in various in vitro and animal models (Guo et al., 2018; Singh et al., 2018; Tang and Amar, 2016; Yuan et al., 2011). A study in C. elegans reported that kavain increases lifespan by inhibiting advance glycation end-products (AGEs), which are known to suppress lifespan (Chaudhuri et al., 2016; Upadhyay et al., 2014). Another study reported that kavain increases acetylcholine (ACh) transmission at the neuromuscular junction (Kautu et al., 2017). Since loss in ACh transmission and increased formation of AGEs are closely linked to A-pathology, we hypothesized that kavain may protect against A-induced toxicity (Kar et al., 2004; Li et al., 2013). We tested kavain in the C. elegans GMC101 strain that over-expresses human Ain body wall muscle cells (McColl et al., 2012). Kavain at a concentration of 40 and 80 M was shown to increase lifespan, thus we decided to use a dose between these ranges (Upadhyay et al., 2014). We observed GMC101 animals fed 50 M kavain showed significantly less paralysis when shifted to the higher permissive temperature (25o C). The result shows that kavain suppresses A-induced proteotoxicity.

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).

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.