{alpha}2A adrenergic receptor mediated antiepileptic effects via G{alpha}o proteins

Activation of G protein coupled α2 adrenergic receptors (AR) by epinephrine (EPI) inhibits epileptiform activity in the mouse hippocampal CA3 region. The specific mechanism underlying this action is unclear. Electrophysiological evidence suggests that the site of action is the recurrent pre‐synaptic CA3 hippocampal pyramidal glutamatergic terminals. This study investigated which subtypes of α2ARs and G‐proteins (Gαo or Gαi) are involved in this particular response. The antiepileptic effects of EPI were assessed using field recordings of hippocampal CA3 epileptiform burst frequencies. Using subtype selective α2AR antagonists, we determined that this effect of EPI was mediated by the α2A AR subtype. Next, using mice with G□ subunit (G184S) knock‐ins that prevent inhibition by regulators of G‐protein signaling, we found enhanced α2A AR effects with mutant Gαo but not Gαi2. These findings indicate that EPI's antiepileptic effect in the hippocampal CA3 region is through an α2AAR Gαo mediated pathway under inhibitory control by RGS proteins. This suggests a role for RGS inhibitors as a novel antiepileptic drug therapy. Supported in part by the American Physiological Society, ND EPSCoR EPS‐0447679, NSF CAREER 0347259, NSF REU Site 0639227, NIH P20 RR0167141 from the NCRR, and NIH 5RO1GM039561.