Modulation of Tonic GABA Currents by Anion Channel and Connexin Hemichannel Antagonists

Christopher B Ransom; Zucheng Ye; William J Spain; George B Richerson

doi:10.1007/s11064-017-2246-4

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Modulation of Tonic GABA Currents by Anion Channel and Connexin Hemichannel Antagonists

Journal article

Peer reviewed

Modulation of Tonic GABA Currents by Anion Channel and Connexin Hemichannel Antagonists

Christopher B Ransom, Zucheng Ye, William J Spain and George B Richerson

Neurochemical research, Vol.42(9), pp.2551-2559

09/2017

DOI: 10.1007/s11064-017-2246-4

PMCID: PMC9013204

PMID: 28401401

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https://www.ncbi.nlm.nih.gov/pmc/articles/9013204View

Open Access

Abstract

Anion channels and connexin hemichannels are permeable to amino acid neurotransmitters. It is hypothesized that these conductive pathways release GABA, thereby influencing ambient GABA levels and tonic GABAergic inhibition. To investigate this, we measured the effects of anion channel/hemichannel antagonists on tonic GABA currents of rat hippocampal neurons. In contrast to predictions, blockade of anion channels and hemichannels with NPPB potentiated tonic GABA currents of neurons in culture and acute hippocampal slices. In contrast, the anion channel/hemichannel antagonist carbenoxolone (CBX) inhibited tonic currents. These findings could result from alterations of ambient GABA concentration or direct effects on GABA receptors. To test for effects on GABA receptors, we measured currents evoked by exogenous GABA. Coapplication of NPPB with GABA potentiated GABA-evoked currents. CBX dose-dependently inhibited GABA-evoked currents. These results are consistent with direct effects of NPPB and CBX on GABA receptors. GABA release from hippocampal cell cultures was directly measured using HPLC. Inhibition of anion channels with NPPB or CBX did not affect GABA release from cultured hippocampal neurons. NPPB reduced GABA release from pure astrocytic cultures by 21%, but the total GABA release from astrocytes was small compared to that of mixed cultures. These data indicate that drugs commonly used to antagonize anion channels and connexin hemichannels may affect tonic currents via direct effects on GABA receptors and have negligible effects on ambient GABA concentrations. Interpretation of experiments using NPPB or CBX should include consideration of their effects on tonic GABA currents.

Animals, Newborn

Connexins - antagonists & inhibitors

Voltage-Dependent Anion Channels - physiology

Connexins - physiology

Cells, Cultured

Nitrobenzoates - pharmacology

Rats

gamma-Aminobutyric Acid - pharmacology

Male

Voltage-Dependent Anion Channels - antagonists & inhibitors

Hippocampus - drug effects

Rats, Sprague-Dawley

Carbenoxolone - pharmacology

Animals

Aminobenzoates - pharmacology

Receptors, GABA-A - physiology

Female

Hippocampus - physiology

Organ Culture Techniques

GABA-A Receptor Antagonists - pharmacology

Details

Title: Subtitle: Modulation of Tonic GABA Currents by Anion Channel and Connexin Hemichannel Antagonists
Creators: Christopher B Ransom - Department of Physiology and Biophysics, University of Washington, Seattle, WA, USA. cbr5@uw.edu
Zucheng Ye - Department of Neurology, University of Washington, Seattle, WA, 98105, USA
William J Spain - Department of Physiology and Biophysics, University of Washington, Seattle, WA, USA
George B Richerson - Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA, USA
Resource Type: Journal article
Publication Details: Neurochemical research, Vol.42(9), pp.2551-2559
DOI: 10.1007/s11064-017-2246-4
PMID: 28401401
PMCID: PMC9013204
NLM abbreviation: Neurochem Res
ISSN: 0364-3190
eISSN: 1573-6903
Publisher: United States
Grant note: R01 NS043288 / NINDS NIH HHS R01NS43288 / NINDS NIH HHS 1IK2BX001307-01A1 / U.S. Department of Veterans Affairs 1 IO1BX002745-01A1 / U.S. Department of Veterans Affairs 101BX000386 / U.S. Department of Veterans Affairs
Language: English
Date published: 09/2017
Academic Unit: Neurology; Molecular Physiology and Biophysics; Iowa Neuroscience Institute; Neurosurgery
Record Identifier: 9984070393502771

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