ArticleProceedings of the National Academy of Sciences of the United States of America2016
Osmoregulatory inositol transporter SMIT1 modulates electrical activity by adjusting PI(4,5)P2 levels.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 60 papers, 1 of them a synthesis that pooled it.
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Who cites it
60 citing papers in PubMed, 1 synthesis or guideline pooled it, 85 citations in OpenAlex.
- Assessing the causal association between human blood metabolites and the risk of epilepsy.Journal of translational medicine · 2022Pooled it
- The SLC-ome of membrane transport: from molecular discovery to physiology and clinical applications.Physiological reviews · 2026Review
- Identification of Sodium/Myo-Inositol Transporter 1 as a Major Determinant of Arterial Contractility.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- Scyllo-Inositol as a Neuroactive Agent: From Pharmacokinetics to Neuroprotective and Antiepileptic Effects.Nutrients · 2026Review
- A patient with a rare metabolic disease and myo-inositol administration leading to a new treatment for epilepsy.Molecular genetics and metabolism · 2026Article
- Sequential membrane remodeling by cholesterol distinctly modulates HCN channels in naïve and neuropathic DRG neurons.The Journal of general physiology · 2026Article
- Sodium-myo-inositol cotransporter-1, SMIT1, promotes cardiac hypertrophy and fibrosis induced by pressure overload in mice.Cardiovascular research · 2026Article
- Cell-specific isotope labeling identifiesbioRxiv : the preprint server for biology · 2026Article
- Canine Cognitive Dysfunction and Alzheimer's Disease: Pathophysiological Relationships and the Impact of Glymphatic System Impairment on Neurodegeneration.Veterinary sciences · 2026Review
- Dose-Dependent Effects of Myo-Inositol on Kainic Acid-Induced Epilepsy: Electrophysiological, Behavioral, Transcriptomic, and DNA Methylome Studies.International journal of molecular sciences · 2025Article
- Molecular and developmental deficits in Smith-Magenis syndrome human stem cell-derived cortical neural models.American journal of human genetics · 2025Article
- The Use of Synaptic Extracellular Myo-Inositol to Treat Developmental and Epileptic Encephalopathy.Annals of the Child Neurology Society · 2025Article
- Voltage sensor conformations induced by LQTS-associated mutations in hERG potassium channels.Nature communications · 2025Article
- An Allosteric Model for Electromechanical Coupling in Cardiac CNBD Channels.bioRxiv : the preprint server for biology · 2025Article
- Evolutionary history and seascape genomics of Harbour porpoises (Phocoena phocoena) across environmental gradients in the North Atlantic and adjacent waters.Molecular ecology resources · 2025Article
- SLC5A3 depletion promotes apoptosis by inducing mitochondrial dysfunction and mitophagy in gemcitabine-resistant pancreatic cancer cells.Cell death & disease · 2025Article
- Preventing epileptogenesis by interaction between inositol isomers and proteins.Epilepsia open · 2025Article
- Ion channel traffic jams: the significance of trafficking deficiency in long QT syndrome.Cell discovery · 2025Review
- Inositol metabolism as a broad-spectrum antiviral target.Frontiers in microbiology · 2025Review
- Membrane lipid nanodomains modulate HCN pacemaker channels in nociceptor DRG neurons.Nature communications · 2024Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
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)P2]. 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 myo-inositol supplementation enlarged intracellular PI(4,5)P2 pools, modulated several PI(4,5)P2-dependent ion channels including KCNQ2/3 channels, and attenuated the action potential firing of superior cervical ganglion neurons. Further experiments using the rapamycin-recruitable phosphatase Sac1 to hydrolyze PI(4)P and the P4M probe to visualize PI(4)P suggested that PI(4)P levels increased after myo-inositol supplementation with SMIT1 expression. Elevated relative levels of PIP and PIP2 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)P2 setpoint. We demonstrate a previously unrecognized linkage between extracellular osmotic changes and the electrical properties of excitable cells.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.