Metabolic control of vesicular glutamate transport and release

Neuron. 2010 Oct 6;68(1):99-112. doi: 10.1016/j.neuron.2010.09.002.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 4-Aminopyridine / pharmacology
  • Acetoacetates / pharmacology
  • Animals
  • Astrocytes / drug effects
  • Astrocytes / physiology
  • Behavior, Animal
  • Cells, Cultured
  • Chlorides / metabolism
  • Chromatography, High Pressure Liquid / methods
  • Disease Models, Animal
  • Dopamine / metabolism
  • Dose-Response Relationship, Drug
  • Embryo, Mammalian
  • Excitatory Postsynaptic Potentials / drug effects
  • Exocytosis / drug effects
  • Exocytosis / genetics
  • Gene Expression Regulation
  • Glutamic Acid / metabolism*
  • Hippocampus / cytology
  • Humans
  • In Vitro Techniques
  • Ketone Bodies
  • Membrane Potential, Mitochondrial / drug effects
  • Membrane Potential, Mitochondrial / genetics
  • Mice
  • Mice, Inbred C57BL
  • Microdialysis / methods
  • Models, Biological
  • Neurons / drug effects
  • Neurons / metabolism*
  • Patch-Clamp Techniques / methods
  • Potassium Channel Blockers / pharmacology
  • Rats
  • Seizures / chemically induced
  • Seizures / physiopathology
  • Synaptic Vesicles / metabolism
  • Vesicular Glutamate Transport Protein 2 / chemistry
  • Vesicular Glutamate Transport Protein 2 / genetics
  • Vesicular Glutamate Transport Protein 2 / metabolism*

Substances

  • Acetoacetates
  • Chlorides
  • Ketone Bodies
  • Potassium Channel Blockers
  • Vesicular Glutamate Transport Protein 2
  • Glutamic Acid
  • acetoacetic acid
  • 4-Aminopyridine
  • Dopamine