Nonvesicular Inhibitory Neurotransmission via Reversal of the GABA Transporter GAT-1

Yuanming Wu; Wengang Wang; Ana Díez-Sampedro; George B Richerson

doi:10.1016/j.neuron.2007.10.021

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Nonvesicular Inhibitory Neurotransmission via Reversal of the GABA Transporter GAT-1

Journal article

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Nonvesicular Inhibitory Neurotransmission via Reversal of the GABA Transporter GAT-1

Yuanming Wu, Wengang Wang, Ana Díez-Sampedro and George B Richerson

Neuron (Cambridge, Mass.), Vol.56(5), pp.851-865

2007

DOI: 10.1016/j.neuron.2007.10.021

PMCID: PMC2156040

PMID: 18054861

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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.

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Details

Title: Subtitle: Nonvesicular Inhibitory Neurotransmission via Reversal of the GABA Transporter GAT-1
Creators: Yuanming Wu - Department of Neurology, Yale University School of Medicine, New Haven, CT 06510, USA
Wengang Wang - Department of Neurology, Yale University School of Medicine, New Haven, CT 06510, USA
Ana Díez-Sampedro - Department of Neurology, Yale University School of Medicine, New Haven, CT 06510, USA
George B Richerson - Department of Neurology, Yale University School of Medicine, New Haven, CT 06510, USA
Resource Type: Journal article
Publication Details: Neuron (Cambridge, Mass.), Vol.56(5), pp.851-865
Publisher: Elsevier Inc
DOI: 10.1016/j.neuron.2007.10.021
PMID: 18054861
PMCID: PMC2156040
ISSN: 0896-6273
eISSN: 1097-4199
Language: English
Date published: 2007
Academic Unit: Neurology; Molecular Physiology and Biophysics; Iowa Neuroscience Institute; Neurosurgery
Record Identifier: 9984020759002771

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