Nonvesicular inhibitory neurotransmission via reversal of the GABA transporter GAT-1

Neuron. 2007 Dec 6;56(5):851-65. doi: 10.1016/j.neuron.2007.10.021.

Abstract

GABA transporters play an important but poorly understood role in neuronal inhibition. They can reverse, but this is widely thought to occur only under pathological conditions. Here we use a heterologous expression system to show that the reversal potential of GAT-1 under physiologically relevant conditions is near the normal resting potential of neurons and that reversal can occur rapidly enough to release GABA during simulated action potentials. We then use paired recordings from cultured hippocampal neurons and show that GABAergic transmission is not prevented by four methods widely used to block vesicular release. This nonvesicular neurotransmission was potently blocked by GAT-1 antagonists and was enhanced by agents that increase cytosolic [GABA] or [Na(+)] (which would increase GAT-1 reversal). We conclude that GAT-1 regulates tonic inhibition by clamping ambient [GABA] at a level high enough to activate high-affinity GABA(A) receptors and that transporter-mediated GABA release can contribute to phasic inhibition.

Publication types

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

MeSH terms

  • Action Potentials / drug effects
  • Action Potentials / physiology
  • Animals
  • CHO Cells
  • Cells, Cultured
  • Chlorides / metabolism
  • Cricetinae
  • Cricetulus
  • Cytosol / drug effects
  • Cytosol / metabolism
  • Electrophysiology
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / physiology
  • GABA Plasma Membrane Transport Proteins / genetics
  • GABA Plasma Membrane Transport Proteins / physiology
  • GABA Uptake Inhibitors*
  • Hippocampus / cytology
  • Hippocampus / drug effects
  • Hippocampus / physiology
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Patch-Clamp Techniques
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, GABA-A / drug effects
  • Receptors, GABA-A / physiology
  • Sodium / metabolism
  • Sodium / physiology
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology*
  • Synaptic Vesicles / drug effects
  • Synaptic Vesicles / physiology*
  • Thermodynamics
  • Transfection
  • gamma-Aminobutyric Acid / metabolism*
  • gamma-Aminobutyric Acid / physiology

Substances

  • Chlorides
  • GABA Plasma Membrane Transport Proteins
  • GABA Uptake Inhibitors
  • Receptors, GABA-A
  • gamma-Aminobutyric Acid
  • Sodium