RGS7 Protein Suppression of Gao Protein‐Mediated α2A‐Adrenergic Receptor Inhibition of Mouse Hippocampal CA3 Epileptiform Activity

Abstract

G‐protein coupled α2 adrenergic receptor (AR) activation by epinephrine (EPI) inhibits epileptiform activity in the mouse hippocampal CA3 region. The mechanism underlying this action is unclear. This study investigated which subtypes of α2ARs, G‐proteins (Gαo or Gαi), and RGS proteins were involved in this response using recordings of hippocampal CA3 epileptiform bursts in mouse brain slices. First, we determined that this effect was mediated by the α2AAR subtype as the inhibitory action of EPI on epileptiform burst frequency was abolished in slices from α2AAR, but not α2CAR, knockout mice. Next, using transgenic mice with the G184S Gnai2 allele (knock‐ins) which interrupts G‐protein α unit binding to regulators of G‐protein signaling (RGS), we found that the α2AAR antiepileptic effects of EPI were enhanced in hippocampal slices from mutant Gαo mice but not Gαi2 mice. Finally, hypomorph mice with very low RGS7 protein levels were found to have increased α2AAR‐mediated hippocampal antiepileptic actions compared to their littermate controls. These results indicate that the EPI‐mediated inhibition of mouse hippocampal CA3 epileptiform burst activity is through an α2AAR/Gαo‐mediated pathway under strong inhibitory control by proteins of the RGS7 family. This suggests a possible role for selective α2AAR agonists or RGS7 inhibitors as a novel antiepileptic drug therapy.