The yeast inositol monophosphatase is a lithium‐ and sodium‐sensitive enzyme encoded by a non‐essential gene pair

Lopez, Félicie; Leube, Martin P.; Gil-Mascarell, Rosario; Navarro-Aviñó, Juan; Serrano, Ramón

doi:10.1046/j.1365-2958.1999.01267.x

Cited by 55 publications

(48 citation statements)

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“…2C). The dispensable nature of TTX-7/IMPase is consistent with the lack of a phenotype in knockout mutants of IMPases in yeast (Lopez et al 1999). In C. elegans, the regulation of inositol trisphosphate signaling is essential for ovulation and defecation (Clandinin et al 1998;Dal Santo et al 1999).…”

Section: Loss Of Ttx-7/impase Causes Specific Defects In Ria Interneumentioning

confidence: 53%

“…Although exogenously applied lithium was reported to reduce the amount of inositol in rat brain (Allison and Stewart 1971), the relationship between the reduction of inositol and the therapeutic effect of lithium is still inconclusive because the actual site of lithium action in brain is unknown and lithium affects molecules other than IMPase Shaldubina et al 2001;Jiang et al 2005). Also, despite the strong emphasis on the critical role of IMPase in inositol production, IMPase is dispensable in yeast (Lopez et al 1999), and other lithium-insensitive activities were found to dephosphorylate inositol monophosphates in Dictyostelium (Van Dijken et al 1996). Thus, the function of IMPase in vivo remains largely unknown.…”

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confidence: 99%

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Inositol monophosphatase regulates localization of synaptic components and behavior in the mature nervous system of C. elegans

et al. 2006

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Although recent studies have provided significant molecular insights into the establishment of neuronal polarity in vitro, evidence is lacking on the corresponding phenomena in vivo, including correct localization of synaptic components and the importance of this process for function of the nervous system as a whole. RIA interneurons act as a pivotal component of the neural circuit for thermotaxis behavior in the nematode Caenorhabditis elegans and provide a suitable model to investigate these issues, having a neurite clearly divided into pre-and post-synaptic regions. In a screen for thermotaxis mutants, we identified the gene ttx-7, which encodes myo-inositol monophosphatase (IMPase), an inositol-producing enzyme regarded as a bipolar disorder-relevant molecule for its lithium sensitivity. Here we show that mutations in ttx-7 cause defects in thermotaxis behavior and localization of synaptic proteins in RIA neurons in vivo. Both behavioral and localization defects in ttx-7 mutants were rescued by expression of IMPase in adults and by inositol application, and the same defects were mimicked by lithium treatment in wild-type animals. These results suggest that IMPase is required in central interneurons of the mature nervous system for correct localization of synaptic components and thus for normal behavior.[Keywords: C. elegans; thermotaxis behavior; protein localization; synapse; myo-inositol monophosphatase; lithium] Supplemental material is available at http://www.genesdev.org. Received April 19, 2006; revised version accepted October 23, 2006. Neurons are the most highly polarized animal cell type and are composed of several subcellular compartments, including axons, dendrites, and cell bodies, each of which has its own molecular and physiological characteristics. How these polarized compartments are established has been extensively investigated using cultured hippocampal neurons as a model system (Dotti and Banker 1987;Dotti et al. 1988). Recent studies have demonstrated that GSK-3␤ and small GTPase-mediated signaling pathways are critical in assigning axonal fate to the immature neurite in hippocampal neurons (Arimura and Kaibuchi 2005;Jiang et al. 2005). The established axonal compartment is physically separated from the cell body by a molecular diffusional barrier, which is at least partly responsible for maintaining the distinct character of these two compartments (Nakada et al. 2003). However, it remains to be determined whether these mechanisms are common to all neuronal types or other mechanisms exist as well. Furthermore, to understand the physiological importance of polarization and consequent subcellular heterogeneity such as localization of synaptic proteins, it is essential to evaluate how these subcellular phenomena in vivo correlate with the function of neurons and the nervous system as a whole.The nematode Caenorhabditis elegans has a simple nervous system that consists of 302 neurons, the synaptic connectivity of which has been described in its entirety by electron microscopy (White et al...

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Section: Loss Of Ttx-7/impase Causes Specific Defects In Ria Interneumentioning

confidence: 53%

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Inositol monophosphatase regulates localization of synaptic components and behavior in the mature nervous system of C. elegans

et al. 2006

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“…A likely mechanism for the lithium-induced decrease is via inhibition of inositol monophosphatase activity (17,31,34). We propose that valproate leads to decreased inositol by inhibition of the Ins-1-P synthase reaction.…”

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confidence: 92%

Lithium and Valproate Decrease Inositol Mass and Increase Expression of the Yeast INO1 and INO2Genes for Inositol Biosynthesis

Vaden¹,

Ding²,

Peterson

et al. 2001

Journal of Biological Chemistry

115

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Bipolar affective disorder (manic-depressive illness)is a chronic, severe, debilitating illness affecting 1-2% of the population. The Food and Drug Administration-approved drugs lithium and valproate are not completely effective in the treatment of this disorder, and the mechanisms underlying their therapeutic effects have not been established. We are employing genetic and molecular approaches to identify common targets of lithium and valproate in the yeast Saccharomyces cerevisiae. We show that both drugs affect molecular targets in the inositol metabolic pathway. Lithium and valproate cause a decrease in intracellular myo-inositol mass and an increase in expression of both a structural (INO1) and a regulatory (INO2) gene required for inositol biosynthesis. The opi1 mutant, which exhibits constitutive expression of INO1, is more resistant to inhibition of growth by lithium but not by valproate, suggesting that valproate may inhibit the Ino1p-catalyzed synthesis of inositol 1-phosphate. Consistent with this possibility, growth in valproate leads to decreased synthesis of inositol monophosphate. Thus, both lithium and valproate perturb regulation of the inositol biosynthetic pathway, albeit via different mechanisms. This is the first demonstration of increased expression of genes in the inositol biosynthetic pathway by both lithium and valproate. Because inositol is a key regulator of many cellular processes, the effects of lithium and valproate on inositol synthesis have far-reaching implications for predicting genetic determinants of responsiveness and resistance to these agents.Bipolar disorder, or manic-depressive illness, is a common condition with a lifetime prevalence of 1-2% (1). It is characterized by recurring bouts of mania and depression, which have deleterious effects on career and interpersonal relationships. Approximately 15% of those afflicted commit suicide, and mortality rates because of physical disorders are also increased (2, 3). For decades, lithium has been the most effective agent for the treatment of bipolar illness (4). Despite the marked benefit that many patients obtain from lithium therapy, 20 -40% of patients fail to show a satisfactory antimanic response to lithium, and many patients suffer significant morbidity (5). More recently, the branched fatty acid valproate has been used for treatment of bipolar disorder (6). Like lithium, it is not completely effective, and the molecular mechanisms underlying its therapeutic effects have not been elucidated. Lithium and valproate exert a variety of biochemical effects, only some of which are likely to be related to their therapeutic mechanisms of action. Identifying common targets of lithium and valproate is an approach that may more directly address the therapeutic mechanisms underlying their efficacy (7-11).The inositol depletion hypothesis proposes that lithium acts by depletion of inositol from the brain. This is based on the observed uncompetitive inhibition of inositol monophosphatases by lithium, resulting in decreased inositol, an i...

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“…These results suggest that clustering of metabolic genes might facilitate fungal adaptation to changing environments both through the acquisition and loss of metabolic capacities. F ungal genes involved in successive steps of a pathway are frequently physically clustered (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). Evolutionary analysis of several different fungal gene clusters has shown that they have originated through different mechanisms (13)(14)(15)(16).…”

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Multiple GAL pathway gene clusters evolved independently and by different mechanisms in fungi

Slot

Rokas

2010

Proc. Natl. Acad. Sci. U.S.A.

151

158

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A notable characteristic of fungal genomes is that genes involved in successive steps of a metabolic pathway are often physically linked or clustered. To investigate how such clusters of functionally related genes are assembled and maintained, we examined the evolution of gene sequences and order in the galactose utilization (GAL) pathway in whole-genome data from 80 diverse fungi. We found that GAL gene clusters originated independently and by different mechanisms in three unrelated yeast lineages. Specifically, the GAL cluster found in Saccharomyces and Candida yeasts originated through the relocation of native unclustered genes, whereas the GAL cluster of Schizosaccharomyces yeasts was acquired through horizontal gene transfer from a Candida yeast. In contrast, the GAL cluster of Cryptococcus yeasts was assembled independently from the Saccharomyces/Candida and Schizosaccharomyces GAL clusters and coexists in the Cryptococcus genome with unclustered GAL paralogs. These independently evolved GAL clusters represent a striking example of analogy at the genomic level. We also found that species with GAL clusters exhibited significantly higher rates of GAL pathway loss than species with unclustered GAL genes. These results suggest that clustering of metabolic genes might facilitate fungal adaptation to changing environments both through the acquisition and loss of metabolic capacities. F ungal genes involved in successive steps of a pathway are frequently physically clustered (1-12). Evolutionary analysis of several different fungal gene clusters has shown that they have originated through different mechanisms (13-16). For example, the DAL cluster for allantoin utilization in Saccharomyces cerevisiae and close relatives originated through adaptive gene relocation (13), whereas a nitrate assimilation cluster in Trichoderma originated through horizontal gene transfer (14). However, it is unclear how these mechanisms shape the assembly of gene clusters, or how the evolutionary trajectories differ between species containing clusters and species in which the genes in a pathway are scattered across the genome.To better understand the origins and maintenance of gene clusters over a large evolutionary timescale and a range of ecological conditions, we investigated the evolution of the Leloir galactose utilization (GAL) pathway in fungi. The detailed knowledge on GAL pathway function in S. cerevisiae (15, 16), and the abundance of genomic data from a wide diversity of fungal species (17), make it an excellent model pathway to address these questions. Furthermore, the relative galactose content varies substantially among different plant substrata (from hundreds of mg/g legume seeds and algal mats to less than 1 mg/g in some fruits) (18-21), suggesting that the natural substrates of fungi have likely provided ample opportunity for populations to evolve niche-dependent adaptations for galactose utilization.The protein products of three GAL genes (GAL1, GAL7, and GAL10) are involved in four enzymatic steps (22). In the first s...

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The yeast inositol monophosphatase is a lithium‐ and sodium‐sensitive enzyme encoded by a non‐essential gene pair

Cited by 55 publications

References 60 publications

Inositol monophosphatase regulates localization of synaptic components and behavior in the mature nervous system of C. elegans

Inositol monophosphatase regulates localization of synaptic components and behavior in the mature nervous system of C. elegans

Lithium and Valproate Decrease Inositol Mass and Increase Expression of the Yeast INO1 and INO2Genes for Inositol Biosynthesis

Multiple GAL pathway gene clusters evolved independently and by different mechanisms in fungi

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