Gαo proteins regulate the α2A adrenergic receptor‐mediated inhibitory effects of epinephrine in the mouse hippocampal CA3 region

Abstract

Activation of α2A adrenergic receptors by epinephrine (EPI) attenuates seizure activity in the rat hippocampal CA3 region. Questions concerning the specific mechanism of this action are whether the α2A receptors are located pre‐ or post‐synaptically, and what subtype of G protein is coupled to this receptor. Evidence suggests that pre‐synaptic terminals of the recurrent axon collateral on pyramidal cells are involved; we hypothesize that the α2A receptors are located pre‐synaptically. We used transgenic mice with knock‐ins of the inhibitory regulators of G‐protein signaling (RGS)‐insensitive G183S Gnai2 allele for either the pre‐synaptic Gαo or the post‐synaptic Gαi2 protein subtype. EPI's anti‐epileptic effects were assessed with electrophysiological recordings in brain slices from control mice, modified Gαo mice, and modified Gαi2 mice.The EC50 of EPI was not significantly different between age‐matched C57BL/6J control and modified Gαi2 mice. In contrast, EPI was significantly more potent (>7‐fold) in the Gαo mice than the littermate controls. These results suggest that the pre‐synaptic Gαo protein and not the post‐synaptic Gαi2 protein mediates EPI's inhibition of hippocampal CA3 epileptiform activity. These findings could lead to new strategies for treating epilepsy. Supported by ND EPSCoR, NSF CAREER 0347259, NSF REU Site 0639227, NIH 5RO1GM039561, NIH P20 RR016741 from the INBRE Program, APS.