Metabolic Control of Vesicular Glutamate Transport and Release

Narinobu Juge, John A. Gray, Hiroshi Omote, Takaaki Miyaji, Tsuyoshi Inoue, Chiaki Hara, Hisayuki Uneyama, Robert H. Edwards, Roger A. Nicoll, Yoshinori Moriyama

Research output: Contribution to journalArticlepeer-review

296 Citations (Scopus)


Fasting has been used to control epilepsy since antiquity, but the mechanism of coupling between metabolic state and excitatory neurotransmission remains unknown. Previous work has shown that the vesicular glutamate transporters (VGLUTs) required for exocytotic release of glutamate undergo an unusual form of regulation by Cl-. Using functional reconstitution of the purified VGLUTs into proteoliposomes, we now show that Cl- acts as an allosteric activator, and the ketone bodies that increase with fasting inhibit glutamate release by competing with Cl- at the site of allosteric regulation. Consistent with these observations, acetoacetate reduced quantal size at hippocampal synapses and suppresses glutamate release and seizures evoked with 4-aminopyridine in the brain. The results indicate an unsuspected link between metabolic state and excitatory neurotransmission through anion-dependent regulation of VGLUT activity.

Original languageEnglish
Pages (from-to)99-112
Number of pages14
Issue number1
Publication statusPublished - Oct 6 2010

ASJC Scopus subject areas

  • General Neuroscience


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