The transmembrane sodium gradient influences ambient GABA concentration by altering the equilibrium of GABA transporters

Yuanming Wu; Wengang Wang; George B Richerson

doi:10.1152/jn.00545.2006

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The transmembrane sodium gradient influences ambient GABA concentration by altering the equilibrium of GABA transporters

Journal article

Peer reviewed

The transmembrane sodium gradient influences ambient GABA concentration by altering the equilibrium of GABA transporters

Yuanming Wu, Wengang Wang and George B Richerson

Journal of neurophysiology, Vol.96(5), pp.2425-2436

11/2006

DOI: 10.1152/jn.00545.2006

PMID: 16870837

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Abstract

Tonic inhibition is widely believed to be caused solely by "spillover" of GABA that escapes the synaptic cleft and activates extrasynaptic GABA(A) receptors. However, an exclusively vesicular source is not consistent with the observation that tonic inhibition can still occur after blocking vesicular release. Here, we made patch-clamp recordings from neurons in rat hippocampal cultures and measured the tonic current that was blocked by bicuculline or gabazine. During perforated patch recordings, the tonic GABA current was decreased by the GAT1 antagonist SKF-89976a. Zero calcium solution did not change the amount of tonic current, despite a large reduction in vesicular GABA release. Perturbations that would be expected to alter the transmembrane sodium gradient influenced the tonic current. For example, in zero calcium Ringer, TTX (which can decrease cytosolic [Na(+)]) reduced tonic current, whereas veratridine (which can increase cytosolic [Na(+)]) increased tonic current. Likewise, removal of extracellular sodium led to a large increase in tonic current. The increases in tonic current induced by veratridine and sodium removal were completely blocked by SKF89976a. When these experiments were repeated in hippocampal slices, similar results were obtained except that a GAT1- and GAT3-independent nonvesicular source(s) of GABA was found to contribute to the tonic current. We conclude that multiple sources can contribute to ambient GABA, including spillover and GAT1 reversal. The source of GABA release may be conceptually less important in determining the amount of tonic inhibition than the factors that control the equilibrium of GABA transporters.

Animals, Newborn

gamma-Aminobutyric Acid - metabolism

Calcium Signaling - physiology

Cells, Cultured

Electrophysiology

Rats

Sodium Channels - drug effects

Calcium Channel Blockers - pharmacology

Hippocampus - cytology

Excitatory Postsynaptic Potentials - drug effects

Rats, Sprague-Dawley

Veratridine - pharmacology

Neuroglia - drug effects

Hippocampus - metabolism

Extracellular Space - metabolism

Patch-Clamp Techniques

Animals

Synapses - metabolism

GABA Plasma Membrane Transport Proteins - metabolism

Neuroglia - metabolism

Neurons - metabolism

In Vitro Techniques

Neurons - drug effects

Sodium - physiology

Details

Title: Subtitle: The transmembrane sodium gradient influences ambient GABA concentration by altering the equilibrium of GABA transporters
Creators: Yuanming Wu - Department of Neurology, LCI-712B, Yale University School of Medicine, 15 York St., PO 208018, New Haven, CT 06520-8018, USA
Wengang Wang
George B Richerson
Resource Type: Journal article
Publication Details: Journal of neurophysiology, Vol.96(5), pp.2425-2436
Publisher: United States
DOI: 10.1152/jn.00545.2006
PMID: 16870837
ISSN: 0022-3077
eISSN: 1522-1598
Grant note: NS-43288 / NINDS NIH HHS
Language: English
Date published: 11/2006
Academic Unit: Neurology; Molecular Physiology and Biophysics; Iowa Neuroscience Institute; Neurosurgery
Record Identifier: 9984013916402771

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