Abstract

γ-Aminobutyric acid (GABA) activates two qualitatively different inhibitory mechanisms through ionotropic GABA_A multisubunit chloride channel receptors and metabotropic GABA_B G protein-coupled receptors. Evidence suggests that pharmacologically distinct GABA_B 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 GABA_B gb1 and gb2 receptor genes and identification of the functional GABA_B 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 GABA_B 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 GABA_A 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 GABA_A inhibitory postsynaptic currents. Gabapentin is the first GABA_B receptor subtype-selective agonist identified providing proof of pharmacologically and physiologically distinct receptor subtypes. This selective agonism of postsynaptic GABA_B receptor subtypes by gabapentin in hippocampal neurons may be its key therapeutic advantage as an anticonvulsant.