gamma-Aminobutyric acid type B receptors with specific heterodimer composition and postsynaptic actions in hippocampal neurons are targets of anticonvulsant gabapentin action

gamma -Aminobutyric acid (GABA) activates two qualitatively different inhib itory mechanisms through ionotropic GABA(A) multisubunit chloride channel r eceptors and metabotropic GABA(B) G protein-coupled receptors. Evidence sug gests that pharmacologically distinct GABA(B) receptor subtypes mediate pre synaptic inhibition of neurotransmitter release by reducing Ca2+ conductanc e, and postsynaptic inhibition of neuronal excitability by activating inwar dly rectifying K+ (Kir) conductance. However, the cloning of GABA(B) gb1 an d gb2 receptor genes and identification of the functional GABA(B) gb1-gb2 r eceptor heterodimer have so far failed to substantiate the existence of pha rmacologically distinct receptor subtypes. The anticonvulsant, antihyperalg esic, and anxiolytic agent gabapentin (Neurontin) is a 3-alkylated GABA ana log with an unknown mechanism of action. Here we report that gabapentin is an agonist at the GABA(B) gb1a-gb2 heterodimer coupled to Kir 3.1/3.2 inwar dly rectifying K+ channels in Xenopus laevis oocytes. Gabapentin was practi cally inactive at the human gb1b-gb2 heterodimer, a novel human gb1c-gb2 he terodimer and did not block GABA agonism at these heterodimer subtypes. Gab apentin was not an agonist at recombinant GABA(A) receptors as well. In CA1 pyramidal neurons of rat hippocampal slices, gabapentin activated postsyna ptic K+ currents, probably via the gb1a-gb2 heterodimer coupled to inward r ectifiers, but did not presynaptically depress monosynaptic GABA(A) inhibit ory postsynaptic currents. Gabapentin is the first GABA(B) receptor subtype -selective agonist identified providing proof of pharmacologically and phys iologically distinct receptor subtypes. This selective agonism of postsynap tic GABA(B) receptor subtypes by gabapentin in hippocampal neurons may be i ts key therapeutic advantage as an anticonvulsant.