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

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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 GABAA receptors. To test for effects on GABAA 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 GABAA 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 GABAA 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.

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Acknowledgements

Work was supported by a VA Career Development Award (CBR, 1IK2BX001307-01A1), VA Merit Review awards to CBR (1 IO1BX002745-01A1) and WJS (101BX000386), and by NINDS (GBR, R01NS43288).

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Authors and Affiliations

  1. Epilepsy Center of Excellence, VA Puget Sound HealthCare System, Seattle, WA, 98108, USA

    Christopher B. Ransom & William J. Spain

  2. Department of Neurology, University of Washington, Seattle, WA, 98105, USA

    Christopher B. Ransom, Zucheng Ye & William J. Spain

  3. Department of Physiology and Biophysics, University of Washington, Seattle, WA, USA

    Christopher B. Ransom & William J. Spain

  4. Department of Neurology, University of Iowa, Iowa City, IA, 52242, USA

    George B. Richerson

  5. Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA, USA

    George B. Richerson

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  1. Christopher B. Ransom
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  2. Zucheng Ye
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  3. William J. Spain
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  4. George B. Richerson
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Correspondence to Christopher B. Ransom.

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Ransom, C.B., Ye, Z., Spain, W.J. et al. Modulation of Tonic GABA Currents by Anion Channel and Connexin Hemichannel Antagonists. Neurochem Res 42, 2551–2559 (2017). https://doi.org/10.1007/s11064-017-2246-4

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  • DOI: https://doi.org/10.1007/s11064-017-2246-4

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