Neuroprotective role of Na+/myo-inositol cotransporter against veratridine cytotoxicity.
Na+/myo-inositol cotransporter has been shown to protect cells from the perturbing effects of hypertonic stress by the accumulation of myo-inositol. Here we report a regulatory mechanism for the cotransporter. Induction of myo-inositol cotransporter mRNA was observed after exposure to veratridine, a voltage-gated sodium channel opener. The veratridine-elicited induction was inhibited when Na+ was eliminated from the bath, although calcium chelation failed to modify the gene expression. Veratridine evoked an accumulation of Na+ in the cells, which paralleled the abundance of the mRNA. These results strongly suggested that an increase in Na+ influx due to sodium channel opening affected transcription of the cotransporter gene. Activity of the myo-inositol cotransporter was also up-regulated after veratridine exposure. To clarify the possible roles of myoinositol accumulation under veratridine exposure, we next examined the neurotoxic effects of veratridine when myo-inositol uptake was blocked. Neither 30 microM veratridine nor 500 microM 2-O,C-methylene myo-inositol, a competitive inhibitor of myo-inositol, elicited apparent cytotoxicity. However, a combination of these agents markedly increased cytotoxicity in culture, suggesting that an adequate amount of myo-inositol was necessary when the cells were stimulated with veratridine.
Yamashita
T
T
Department of Anatomy and Neuroscience, Osaka University Medical School Suita, Japan.
Yamauchi
A
A
Miyai
A
A
Taniguchi
M
M
Yoshimine
T
T
Tohyama
M
M
D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D006360:Heat-Shock Proteins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D006982:Hypertonic Solutions / Q000494:pharmacology; D007294:Inositol / Q000493:pharmacokinetics; D008565:Membrane Proteins; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009498:Neurotoxins / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D012964:Sodium / Q000493:pharmacokinetics; D027981:Symporters; D014407:Tumor Cells, Cultured; D014701:Veratridine / Q000037:antagonists & inhibitors* / Q000506:poisoning
D002352:Carrier Proteins; D006360:Heat-Shock Proteins; D006982:Hypertonic Solutions; D008565:Membrane Proteins; D009498:Neurotoxins; D012333:RNA, Messenger; D027981:Symporters; C073884:SLC5A3 protein, human; D007294:Inositol; D014701:Veratridine; D012964:Sodium