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J Neurophysiol. 2013 Feb;109(3):649-58. doi: 10.1152/jn.00784.2011. Epub 2012 Nov 7.

A cGMP-dependent protein kinase (PKG) controls synaptic transmission tolerance to acute oxidative stress at the Drosophila larval neuromuscular junction.

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Department of Biological Sciences, Florida Atlantic University, Boca Raton, FL 33431-0991, USA.


Increasing evidence demonstrates that modulating the cGMP-dependent protein kinase G (PKG) pathway produces an array of behavioral phenotypes in the fruit fly, Drosophila melanogaster. Altering PKG activity, either genetically via the foraging (for) gene or using pharmacology modifies tolerance to acute abiotic stresses such as hyperthermia and hypoxia. PKG signaling has been shown to modulate neuroprotection in many experimental paradigms of acute brain trauma and chronic neurodegenerative diseases. However, relatively little is known about how this stress-induced neuroprotective mechanism affects neural communication. In this study, we investigated the role PKG activity has on synaptic transmission at the Drosophila larval neuromuscular junction (NMJ) during acute oxidative stress and found that the application of 2.25 mM hydrogen peroxide (H(2)O(2)) disrupts synaptic function by rapidly increasing the rate of neuronal failure. Here, we report that reducing PKG activity through either natural genetic variation or an induced mutation of the for gene increases synaptic tolerance during acute oxidative conditions. Furthermore, pharmacological manipulations revealed that neurotransmission is significantly extended during acute H(2)O(2) exposure upon inhibition of the PKG pathway. Conversely, activation of this signaling cascade using either genetics or pharmacology significantly reduced the time until synaptic failure. Therefore, these findings suggest a potential role for PKG activity to regulate the tolerance of synaptic transmission during acute oxidative stress, where inhibition promotes functional protection while activation increases susceptibility to neurotransmission breakdown.

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