Nitric Oxide Directly Activates GABAA Receptor Function Through a cGMP/Protein Kinase‐Independent Pathway in Frog Pituitary Melanotrophs
- 1 August 2001
- journal article
- research article
- Published by Wiley in Journal of Neuroendocrinology
- Vol. 13 (8) , 695-705
- https://doi.org/10.1046/j.1365-2826.2001.00683.x
Abstract
The direct effects of nitric oxide (NO) donors and sulfhydryl‐modifying agents on the GABAA receptor function were examined by perforated patch, whole‐cell and single channel recordings in cultured frog melanotrophs. In amphotericin B‐perforated cells incubated with the soluble guanylyl cyclase inhibitors LY 83583 and ODQ (10−4 M each), the NO donor sodium nitroprusside (SNP) (10−3 M) reversibly increased the current evoked by GABA (5 × 10−6 M). In the whole‐cell configuration, internal application of the oxidizing agent H2O2 (0.05%) potentiated the GABA‐evoked current while the reducing agent 2‐mercaptoethanol (5 × 10−3 M) slightly decreased the current amplitude. In inside‐out patches, GABA (2 × 10−7 M) triggered single channel bursts of openings. Incubation with the NO donors SNP or DEA/NO (10−4 M each) enhanced the open probability of the GABAA receptor channel but did not modify the chloride reversal potential and did not affect the conductance states. The oxidizing agents H2O2 (0.05%) or DTNB (10−4 M) mimicked the stimulatory effect of the NO donors on the open probability while the reducing compounds 2‐mercaptoethanol (5 × 10−3 M) or DTT (10−4 M) markedly attenuated the channel activity. Potentiation of the GABA‐induced single channel activity by SNP or H2O2 was blocked by 2‐mercaptoethanol. Similarly, the potentiating effect produced by DEA/NO or DTNB on the open probability was reversed by DTT. In outside‐out patches, incubation with SNP also significantly enhanced the open probability of single channels activated by GABA (10−6 M). These data indicate that, in frog pituitary melanotrophs, NO potentiates the GABA‐evoked current independently of the cGMP/protein kinase pathway. The effect of NO can be accounted for by S‐nitrosylation/oxidation of thiol groups either directly on the GABAA receptor subunits or on a regulatory protein tightly associated with the GABAA receptor.Keywords
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