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

doi:10.1016/j.neuron.2010.09.002

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

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276 Citations (Scopus)

Abstract

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 language	English
Pages (from-to)	99-112
Number of pages	14
Journal	Neuron
Volume	68
Issue number	1
DOIs	https://doi.org/10.1016/j.neuron.2010.09.002
Publication status	Published - Oct 6 2010

ASJC Scopus subject areas

Neuroscience(all)

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10.1016/j.neuron.2010.09.002

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title = "Metabolic Control of Vesicular Glutamate Transport and Release",

abstract = "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.",

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

note = "Funding Information: We thank Drs. Miki Hiasa and Masafumi Iharada for help in the immunohistochemical study and purification of VGLUT1 and VGLUT3. N.J. was supported by a Research Fellowship from the Japan Society for the Promotion of Science for Young Scientists. J.A.G. was supported by an NIH training grant. This work was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan to Y.M., NIH 5R01MH080379 to R.A.N., NIMH, NIGMS, and NIDA to R.H.E. ",

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AU - Juge, Narinobu

AU - Gray, John A.

AU - Omote, Hiroshi

AU - Miyaji, Takaaki

AU - Inoue, Tsuyoshi

AU - Hara, Chiaki

AU - Uneyama, Hisayuki

AU - Edwards, Robert H.

AU - Nicoll, Roger A.

AU - Moriyama, Yoshinori

N1 - Funding Information: We thank Drs. Miki Hiasa and Masafumi Iharada for help in the immunohistochemical study and purification of VGLUT1 and VGLUT3. N.J. was supported by a Research Fellowship from the Japan Society for the Promotion of Science for Young Scientists. J.A.G. was supported by an NIH training grant. This work was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan to Y.M., NIH 5R01MH080379 to R.A.N., NIMH, NIGMS, and NIDA to R.H.E.

PY - 2010/10/6

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N2 - 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.

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Metabolic Control of Vesicular Glutamate Transport and Release

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