Characterization of the null murine sodium/myo-inositol cotransporter 1 (Smit1 or Slc5a3) phenotype: Myo-inositol rescue is independent of expression of its cognate mitochondrial ribosomal protein subunit 6 (Mrps6) gene and of phosphatidylinositol levels in neonatal brain

Buccafusca, Roberto; Venditti, Charles P.; Kenyon, Lawrence C.; Johanson, Roy A.; Bockstaele, Elisabeth Van; Ren, Jun; Pagliardini, Silvia; Minarcik, Jeremy; Golden, Jeffrey A.; Coady, Michael J.; Greer, John J.; Berry, Gerard T.

doi:10.1016/j.ymgme.2008.05.008

Cited by 38 publications

(50 citation statements)

References 74 publications

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“…To our surprise, the mass spectrometry experiments did not detect a significant increase in total PI levels. This result seems consistent with previous findings that SMIT1 knockout mice (SLC5A3 −/− ) did not exhibit significant loss in PI even though their myo-inositol levels were greatly reduced (14,24). There, myo-inositol supplementation was required to avoid an otherwise lethal knockout phenotype.…”

Section: Discussionsupporting

confidence: 92%

“…There, myo-inositol supplementation was required to avoid an otherwise lethal knockout phenotype. Perhaps because no change of total PI had been seen in these mice the levels of PI(4,5)P 2 and PI(4)P were supposed to be invariant and were not further investigated (24). A large proportion of total PI is located in intracellular organelles, such as the ER (1, 61).…”

Section: Discussionmentioning

confidence: 99%

“…The myo-inositol level in mammalian tissues ranges from 0.1 to 16 mM, depending on the tissue (22,23). It is high in adult brain (millimolar level) and is reduced by 96% in SLC5A3 −/− mice (24). Such mice need to be maintained on myo-inositol supplementation until weaning.…”

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confidence: 99%

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Osmoregulatory inositol transporter SMIT1 modulates electrical activity by adjusting PI(4,5)P₂levels

Dai

Hou

Kruse

et al. 2016

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

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Myo-inositol is an important cellular osmolyte in autoregulation of cell volume and fluid balance, particularly for mammalian brain and kidney cells. We find it also regulates excitability. Myo-inositol is the precursor of phosphoinositides, key signaling lipids including phosphatidylinositol 4,5-bisphosphate [PI(4,5)P 2 ]. However, whether myo-inositol accumulation during osmoregulation affects signaling and excitability has not been fully explored. We found that overexpression of the Na + /myo-inositol cotransporter (SMIT1) and myoinositol supplementation enlarged intracellular PI(4,5)P 2 pools, modulated several PI(4,5)P 2 -dependent ion channels including KCNQ2/3 channels, and attenuated the action potential firing of superior cervical ganglion neurons. Further experiments using the rapamycinrecruitable phosphatase Sac1 to hydrolyze PI(4)P and the P4M probe to visualize PI(4)P suggested that PI(4)P levels increased after myoinositol supplementation with SMIT1 expression. Elevated relative levels of PIP and PIP 2 were directly confirmed using mass spectrometry. Inositol trisphosphate production and release of calcium from intracellular stores also were augmented after myo-inositol supplementation. Finally, we found that treatment with a hypertonic solution mimicked the effect we observed with SMIT1 overexpression, whereas silencing tonicity-responsive enhancer binding protein prevented these effects. These results show that ion channel function and cellular excitability are under regulation by several "physiological" manipulations that alter the PI(4,5)P 2 setpoint. We demonstrate a previously unrecognized linkage between extracellular osmotic changes and the electrical properties of excitable cells.myo-inositol | ion channels | PIP 2 | phosphoinositide | SMIT1

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

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Osmoregulatory inositol transporter SMIT1 modulates electrical activity by adjusting PI(4,5)P₂levels

Dai

Hou

Kruse

et al. 2016

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

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“…In light of these observations, it was a remarkable finding that SMIT1 knockout mice develop normally but die from congenital central apnea due to abnormal respiratory rhythmogenesis (138,195). These mice have more than 90% reduction in brain and more than 80% in whole body myo-inositol content.…”

Section: Phosphatidylinositol Synthesismentioning

confidence: 99%

Phosphoinositides: Tiny Lipids With Giant Impact on Cell Regulation

Balla

2013

Physiological Reviews

1,365

1,655

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Phosphoinositides (PIs) make up only a small fraction of cellular phospholipids, yet they control almost all aspects of a cell's life and death. These lipids gained tremendous research interest as plasma membrane signaling molecules when discovered in the 1970s and 1980s. Research in the last 15 years has added a wide range of biological processes regulated by PIs, turning these lipids into one of the most universal signaling entities in eukaryotic cells. PIs control organelle biology by regulating vesicular trafficking, but they also modulate lipid distribution and metabolism via their close relationship with lipid transfer proteins. PIs regulate ion channels, pumps, and transporters and control both endocytic and exocytic processes. The nuclear phosphoinositides have grown from being an epiphenomenon to a research area of its own. As expected from such pleiotropic regulators, derangements of phosphoinositide metabolism are responsible for a number of human diseases ranging from rare genetic disorders to the most common ones such as cancer, obesity, and diabetes. Moreover, it is increasingly evident that a number of infectious agents hijack the PI regulatory systems of host cells for their intracellular movements, replication, and assembly. As a result, PI converting enzymes began to be noticed by pharmaceutical companies as potential therapeutic targets. This review is an attempt to give an overview of this enormous research field focusing on major developments in diverse areas of basic science linked to cellular physiology and disease.

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“…Disruption of inositol homeostasis is reported to be a factor in bipolar disorder (Shaltiel et al, 2004) and neurodegenerative diseases, including Alzheimer's disease (Miller et al, 1993), Huntington's disease, and Parkinson's disease (Sarkar et al, 2005). Recently, inositol deficiency was shown to induce a neonatally lethal phenotype in mice (Buccafusca et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

d-myo-Inositol-3-Phosphate Affects Phosphatidylinositol-Mediated Endomembrane Function inArabidopsisand Is Essential for Auxin-Regulated Embryogenesis

et al. 2011

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In animal cells, myo-inositol is an important regulatory molecule in several physiological and biochemical processes, including signal transduction and membrane biogenesis. However, the fundamental biological functions of myo-inositol are still far from clear in plants. Here, we report the genetic characterization of three Arabidopsis thaliana genes encoding D-myo-inositol-3-phosphate synthase (MIPS), which catalyzes the rate-limiting step in de novo synthesis of myo-inositol. Each of the three MIPS genes rescued the yeast ino1 mutant, which is defective in yeast MIPS gene INO1, and they had different dynamic expression patterns during Arabidopsis embryo development. Although single mips mutants showed no obvious phenotypes, the mips1 mips2 double mutant and the mips1 mips2 mips3 triple mutant were embryo lethal, whereas the mips1 mips3 and mips1 mips2 +/2 double mutants had abnormal embryos. The mips phenotypes resembled those of auxin mutants. Indeed, the double and triple mips mutants displayed abnormal expression patterns of DR5:green fluorescent protein, an auxin-responsive fusion protein, and they had altered PIN1 subcellular localization. Also, membrane trafficking was affected in mips1 mips3. Interestingly, overexpression of PHOSPHATIDYLINOSITOL SYNTHASE2, which converts myoinositol to membrane phosphatidylinositol (PtdIns), largely rescued the cotyledon and endomembrane defects in mips1 mips3. We conclude that myo-inositol serves as the main substrate for synthesizing PtdIns and phosphatidylinositides, which are essential for endomembrane structure and trafficking and thus for auxin-regulated embryogenesis.

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Characterization of the null murine sodium/myo-inositol cotransporter 1 (Smit1 or Slc5a3) phenotype: Myo-inositol rescue is independent of expression of its cognate mitochondrial ribosomal protein subunit 6 (Mrps6) gene and of phosphatidylinositol levels in neonatal brain

Cited by 38 publications

References 74 publications

Osmoregulatory inositol transporter SMIT1 modulates electrical activity by adjusting PI(4,5)P₂levels

Osmoregulatory inositol transporter SMIT1 modulates electrical activity by adjusting PI(4,5)P₂levels

Phosphoinositides: Tiny Lipids With Giant Impact on Cell Regulation

d-myo-Inositol-3-Phosphate Affects Phosphatidylinositol-Mediated Endomembrane Function inArabidopsisand Is Essential for Auxin-Regulated Embryogenesis

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Characterization of the null murine sodium/myo-inositol cotransporter 1 (Smit1 or Slc5a3) phenotype: Myo-inositol rescue is independent of expression of its cognate mitochondrial ribosomal protein subunit 6 (Mrps6) gene and of phosphatidylinositol levels in neonatal brain

Cited by 38 publications

References 74 publications

Osmoregulatory inositol transporter SMIT1 modulates electrical activity by adjusting PI(4,5)P2levels

Osmoregulatory inositol transporter SMIT1 modulates electrical activity by adjusting PI(4,5)P2levels

Phosphoinositides: Tiny Lipids With Giant Impact on Cell Regulation

d-myo-Inositol-3-Phosphate Affects Phosphatidylinositol-Mediated Endomembrane Function inArabidopsisand Is Essential for Auxin-Regulated Embryogenesis

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Osmoregulatory inositol transporter SMIT1 modulates electrical activity by adjusting PI(4,5)P₂levels

Osmoregulatory inositol transporter SMIT1 modulates electrical activity by adjusting PI(4,5)P₂levels