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General Commentary ARTICLE

Front. Cell. Neurosci., 06 October 2015 | https://doi.org/10.3389/fncel.2015.00401

Commentary: “Nitric oxide releases Cl from acidic organelles in retinal amacrine cells”

  • Institute of Physiology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany

A commentary on
Nitric oxide releases Cl from acidic organelles in retinal amacrine cells

by Krishnan, V., and Gleason, E. (2015). Front. Cell. Neurosci. 9:213. doi: 10.3389/fncel.2015.00213

In their recent article (Krishnan and Gleason, 2015) Vijai Krishnan and Evanna Gleason investigate the cellular mechanisms underlying the shift in the GABA reversal potential upon application of nitric oxide (NO). Functional alteration in GABAergic signaling by alterations in the GABA reversal potential has been identified as an important mechanism of plasticity (Raimondo et al., 2012) and NO is clearly one key substance involved in plasticity (Prast and Philippu, 2001). Therefore, the investigation of the mechanisms behind the NO induced shift in GABAergic effects is an important issue. However, in my opinion the authors neglected a possible explanation of their observations in the discussion section of their recent article.

The detailed investigation in the present article was based on the seminal observation by the same group that moderate concentrations of NO donors induced a slight increase in GABAA receptor mediated responses without affecting the reversal potential, while the application of a saturated NO solution (resulting in “hundreds of nanomolar to low micromolar” NO concentrations) led to a significant shift in the GABA reversal potential (Hoffpauir et al., 2006). The latter effect was independent of the soluble guanylate cyclase, which is elementary for the classical NO signaling pathway, and persisted in nominally Cl-free extracellular solution, suggesting that NO may trigger a Cl release from intracellular stores (Hoffpauir et al., 2006). Further experiments by the authors suggest that a NO-induced intracellular acidification triggers the release of Cl from intracellular compartments (McMains and Gleason, 2011). In the present study they used nominally Cl-free extracellular and intracellular (pipette-) solutions to “wash out both cytosolic and protein-bound Cl” and thereby isolate Cl stores “contained within an intracellular membrane-bound compartment” (Krishnan and Gleason, 2015). These experiments demonstrated that application of NO or NO-donors re-established GABAergic currents under nominally Cl-free conditions, and that this effect was attenuated in the presence of the V-type ATPase inhibitor bafilomycin and was abolished by the uncoupling agent FCCP. From these experimental findings they came to the well supported conclusion, that acidic compartments are a possible source for the NO-induced increase in intracellular Cl anions.

However, when such high NO concentrations are used, it should be considered that the mitochondrial cytochrome c oxidase can reduce NO to nitrite (NO2-), although no information about the maximal rates for this process is available (Sarti et al., 2012). The permeability of NO2- through GABAA receptors is higher than their Cl permeability (Bormann et al., 1987). Thus the intracellular generation of NO2- might contribute to the re-occurrence of inward currents after NO application under nominally Cl-free solutions. Notably, the oxidation of NO to NO2- relies on functional oxidative phosphorylation (Sarti et al., 2012). Thus, the reduction of NO-induced GABA currents by bafilomycin and its abolishment by FCCP (Krishnan and Gleason, 2015) may be caused by the fact, that both substances induce mitochondrial dysfunction via uncoupling (Zhdanov et al., 2012).

Therefore, I suggest that the authors should consider the formation of NO2- as an additional hypothesis to explain their observations. To differentiate between both hypotheses, a conclusive experiment would be to test whether the NO-induced GABA currents in nominally Cl-free intra- and extra-cellular solutions are depletable (indicating a limited intracellular reservoir of Cl ions) or whether repetitive NO applications induced sustained GABA currents (indicating a NO-dependent generation of anions permeable via the GABAA receptor).

Funding

This work was funded by DFG grant KI835/2 to WK.

Conflict of Interest Statement

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References

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Keywords: GABA, nitric oxide, nitrite, amacrine cell, short term plasticity, chloride channels

Citation: Kilb W (2015) Commentary: “Nitric oxide releases Cl from acidic organelles in retinal amacrine cells”. Front. Cell. Neurosci. 9:401. doi: 10.3389/fncel.2015.00401

Received: 11 September 2015; Accepted: 22 September 2015;
Published: 06 October 2015.

Edited by:

Gerald W. Zamponi, University of Calgary, Canada

Reviewed by:

Melanie A. Woodin, University of Toronto, Canada

Copyright © 2015 Kilb. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Werner Kilb, wkilb@uni-mainz.de