New insights into molecular mechanism(s) underlying the presynaptic action of nitric oxide on GABA release |
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Authors: | Alla Tarasenko Olga Krupko Nina Himmelreich |
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Institution: | Department of Neurochemistry, Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, Leontovich Str. 9, Kyiv 01601, Ukraine |
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Abstract: | BackgroundNitric oxide (NO) is an important presynaptic modulator of synaptic transmission. Here, we aimed to correlate the release of the major inhibitory neurotransmitter GABA with intracellular events occurring in rat brain axon terminals during their exposure to NO in the range of nanomolar–low micromolar concentrations.MethodsUsing 3H]GABA and fluorescent dyes (Fluo 4-AM, acridine orange and rhodamine 6G), the following parameters were evaluated: vesicular and cytosolic GABA pools, intracellular calcium concentration, synaptic vesicle acidification, and mitochondrial membrane potential. Diethylamine NONOate (DEA/NO) and S-nitroso-N-acetylpenicillamine (SNAP) were used as NO donors.ResultsDEA/NO and SNAP (in the presence of dithiothreitol (DTT)) stimulated external Ca2 +-independent 3H]GABA release, which was not attributed to a rise in intracellular calcium concentration. 3H]GABA release coincided with increasing GABA level in cytosol and decreasing the vesicular GABA content available for exocytotic release. There was a strong temporal correlation between NO-induced increase in cytosolic GABA] and dissipation of both synaptic vesicle proton gradient and mitochondrial membrane potential. Dissipation was reversible, and recovery of both parameters correlated in time with re-accumulation of 3H]GABA into synaptic vesicles. The molar ratio of DTT to SNAP determined the rate and duration of the recovery processes.ConclusionsWe suggest that NO can stimulate GABA release via GABA transporter reversal resulting from increased GABA levels in cytosol. The latter is reversible and appears to be due to S-nitrosylation of key proteins, which affect the energy status of the pre-synapse.General significanceOur findings provide new insight into molecular mechanism(s) underlying the presynaptic action of nitric oxide on inhibitory neurotransmission. |
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Keywords: | Nitric oxide [3H]GABA release Synaptic vesicle acidification Mitochondrial membrane potential S-nitrosylation Exocytosis |
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