A dual mechanism for impairment of GABAA receptor activity by NMDA receptor activation in rat cerebellum granule cells
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The function of the GABAA receptor has been studied using the whole cell voltage clamp recording technique in rat cerebellum granule cells in culture. Activation of NMDA-type glutamate receptors causes a reduction in the effect of GABA. Full GABAA receptor activity was recovered after washing out NMDA and NMDA action was prevented in a Mg++ containing medium. The NMDA effect was also absent when extracellular Ca++ was replaced by Ba++ and when 10 mM Bapta was present in the intracellular solution. Charge accumulations via voltage activated Ca++ channels greater than the ones via NMDA receptors do not cause any reduction in GABAA receptor function, suggesting that Ca++ influx through NMDA receptor channels is critical for the effect. The NMDA effect was reduced by including adenosine-5′-O-3-thiophosphate (ATP-γ-S) in the internal solution and there was a reduction in the NMDA effect caused by deltamethrin, a calcineurin inhibitor. Part of the NMDA induced GABAA receptor impairment was prevented by prior treatment with L-arginine. Analogously, part of the NMDA effect was prevented by blockage of NO-synthase activity by Nω-nitro-L-arginine. A combination of NO-synthase and calcineurin inhibitors completely eliminated the NMDA action. An analogous result was obtained by combining the NO-synthase inhibitor with the addition of ATP-γ-S to the pipette medium. The additivity of the prevention of the NMDA impairment of GABAA receptor by blocking the L-arginine/NO pathway and inhibiting calcineurin activity suggests an independent involvement of these two pathways in the interaction between NMDA and the GABAA receptor. On the one hand Ca++ influx across NMDA channels activates calcineurin and dephosphorylates the GABAA receptor complex directly or dephosphorylates proteins critical for the function of the receptor. On the other hand, Ca++ influx activates NO-synthase and induces nitric oxide production, which regulates such receptors via protein kinase G activity.
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