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Regulator of G Protein Signaling Protein Suppression of G_o Protein-Mediated _2A Adrenergic Receptor Inhibition of Mouse Hippocampal CA3 Epileptiform Activity

Department of Pharmacology, Physiology and Therapeutics, University of North Dakota, School of Medicine and Health Sciences, Grand Forks, North Dakota (B.L.G., B.W.N., K.X., E.J.L., J.A.P., J.M.W., L.A.O., V.A.D.); Department of Human Genetics, Emory University, Atlanta, Georgia (D.W.); and Department of Pharmacology, University of Michigan, Medical School, Ann Arbor, Michigan (R.A.C., X.H., R.R.N.)

Activation of G protein-coupled ₂ adrenergic receptors (ARs) inhibits epileptiform activity in the hippocampal CA3 region. The specific mechanism underlying this action is unclear. This study investigated which subtype(s) of ₂ARs and G proteins (G_o or G_i) are involved in this response using recordings of mouse hippocampal CA3 epileptiform bursts. Application of epinephrine (EPI) or norepinephrine (NE) reduced the frequency of bursts in a concentration-dependent manner: (-)EPI > (-)NE >>> (+)NE. To identify the ₂AR subtype involved, equilibrium dissociation constants (pK_b) were determined for the selective AR antagonists atipamezole (8.79), rauwolscine (7.75), 2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane hydrochloride (WB-4101; 6.87), and prazosin (5.71). Calculated pK_b values correlated best with affinities determined previously for the mouse _2AAR subtype (r = 0.98, slope = 1.07). Furthermore, the inhibitory effects of EPI were lost in hippocampal slices from _2AAR-but not _2CAR-knockout mice. Pretreatment with pertussis toxin also reduced the EPI-mediated inhibition of epileptiform bursts. Finally, using knock-in mice with point mutations that disrupt regulator of G protein signaling (RGS) binding to G subunits to enhance signaling by that G protein, the EPI-mediated inhibition of bursts was significantly more potent in slices from RGS-insensitive G_o^G184S heterozygous (G_o+/GS) mice compared with either G_i2^G184S heterozygous (G_i2+/GS) or control mice (EC₅₀ = 2.5 versus 19 and 23 nM, respectively). Together, these findings indicate that the inhibitory effect of EPI on hippocampal CA3 epileptiform activity uses an _2AAR/G_o protein-mediated pathway under strong inhibitory control by RGS proteins. This suggests a possible role for RGS inhibitors or selective _2AAR agonists as a novel antiepileptic drug therapy.

Received for publication December 18, 2008.

Accepted for publication February 18, 2009.

Address correspondence to: Dr. Van A. Doze, Department of Pharmacology, Physiology and Therapeutics, School of Medicine and Health Sciences, University of North Dakota, 501 North Columbia Road, Stop 9037, Grand Forks, ND 58202-9037. E-mail: vdoze{at}medicine.nodak.edu

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