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Vol. 59, Issue 1, 144-152, January 2001

gamma -Aminobutyric Acid Type B Receptors with Specific Heterodimer Composition and Postsynaptic Actions in Hippocampal Neurons Are Targets of Anticonvulsant Gabapentin Action

Gordon Y. K. Ng, Sandrine Bertrand, Richard Sullivan, Nathalie Ethier, Jennifer Wang, Jim Yergey, Michel Belley, Laird Trimble, Kevin Bateman, Luanda Alder, Alison Smith, Ruth McKernan, Kathleen Metters, Gary P. O'Neill, Jean-Claude Lacaille, and Terence E. Hébert

Merck Frosst Center for Therapeutic Research, Kirkland, Canada (G.Y.K.N., R.S., J.W., J.Y., M.B., L.T., K.B., K.M., G.P.O.); Centre de recherche en sciences neurologiques et Département de physiologie, Université de Montréal, Montréal, Canada (S.B., J.-C.L.); Institut de Cardiologie de Montréal et le Groupe de Recherche sur le Système Nerveux Autonome, Université de Montréal, Montréal, Canada (N.E., T.E.H.); and Merck Sharp & Dohme Research Laboratories, Terlings Park, Harlow, Essex CM20 2QR, UK (L.A., A.S., R.M.)

gamma -Aminobutyric acid (GABA) activates two qualitatively different inhibitory mechanisms through ionotropic GABAA multisubunit chloride channel receptors and metabotropic GABAB G protein-coupled receptors. Evidence suggests that pharmacologically distinct GABAB receptor subtypes mediate presynaptic inhibition of neurotransmitter release by reducing Ca2+ conductance, and postsynaptic inhibition of neuronal excitability by activating inwardly rectifying K+ (Kir) conductance. However, the cloning of GABAB gb1 and gb2 receptor genes and identification of the functional GABAB gb1-gb2 receptor heterodimer have so far failed to substantiate the existence of pharmacologically distinct receptor subtypes. The anticonvulsant, antihyperalgesic, and anxiolytic agent gabapentin (Neurontin) is a 3-alkylated GABA analog with an unknown mechanism of action. Here we report that gabapentin is an agonist at the GABAB gb1a-gb2 heterodimer coupled to Kir 3.1/3.2 inwardly rectifying K+ channels in Xenopus laevis oocytes. Gabapentin was practically inactive at the human gb1b-gb2 heterodimer, a novel human gb1c-gb2 heterodimer and did not block GABA agonism at these heterodimer subtypes. Gabapentin was not an agonist at recombinant GABAA receptors as well. In CA1 pyramidal neurons of rat hippocampal slices, gabapentin activated postsynaptic K+ currents, probably via the gb1a-gb2 heterodimer coupled to inward rectifiers, but did not presynaptically depress monosynaptic GABAA inhibitory postsynaptic currents. Gabapentin is the first GABAB receptor subtype-selective agonist identified providing proof of pharmacologically and physiologically distinct receptor subtypes. This selective agonism of postsynaptic GABAB receptor subtypes by gabapentin in hippocampal neurons may be its key therapeutic advantage as an anticonvulsant.

Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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