The Role of Ion Channels and Intracellular Signaling Cascades in the Inhibitory Action of WIN 55,212-2 upon Hyperexcitation.

Abstract

Gi-coupled receptors, particularly cannabinoid receptors (CBRs), are considered perspective targets for treating brain pathologies, including epilepsy. However, the precise mechanism of the anticonvulsant effect of the CBR agonists remains unknown. We have found that WIN 55,212-2 (a CBR agonist) suppresses the synchronous oscillations of the intracellular concentration of Ca2+ ions (epileptiform activity) induced in the neurons of rat hippocampal neuron-glial cultures by bicuculline or NH4Cl. As we have demonstrated, the WIN 55,212-2 effect is mediated by CB1R receptors. The agonist suppresses Ca2+ inflow mediated by the voltage-gated calcium channels but does not alter the inflow mediated by NMDA, AMPA, and kainate receptors. We have also found that phospholipase C (PLC), protein kinase C (PKC), and G-protein-coupled inwardly rectifying K+ channels (GIRK channels) are involved in the molecular mechanism underlying the inhibitory action of CB1R activation against epileptiform activity. Thus, our results demonstrate that the antiepileptic action of CB1R agonists is mediated by different intracellular signaling cascades, including non-canonical PLC/PKC-associated pathways.