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

Abstract

␥-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 Ca 2ϩ conductance, and postsynaptic inhibition of neuronal excitability by activating inwardly rectifying K ϩ (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 ϩ 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 ϩ 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.

Endogenous GABA Does Not Mediate the Inhibitory Effects of Gabapentin on Spinal Reflexes in Rats

“…In addition, the preferential effects of baclofen on monosynaptic reflex rather than polysynaptic reflex transmission support this conclusion (17,19). However, presently, there exist several lines of evidence that argue for (28,29) and against (30) the mediation of GABA B receptors in the action of gabapentin. Moreover, gabapentin may reveal a specific agonism of the GABA B -receptor subtypes (29).…”

Mechanisms of the Antinociceptive Action of Gabapentin

“…In the superficial laminae of the spinal cord where nociceptive primary afferent fibers terminate, the predominant subtype of GABA B receptors is the GABA B1a-B2 heterodimeric type (70), which was proposed to be selectively activated by gabapentin (61,62). It is reasonable to suggest that spinal GABA B receptors might be the target of the antinociceptive effect of intrathecal gabapentin (61).…”

“…Sutton et al (69) found that gabapentin decreased the whole cell Ca 2+ current mainly gated by N-type Ca 2+ channels in cultured DRG neurons. The IC 50 of gabapentin in inhibiting Ca 2+ current is simialr to its K D value in the α 2 δ binding (142) and the inhibitiory effect was saturated at a concentration close to the therapeutic plasma concentration of gabapentin in the treatment of epilepsy and neuropathy (10 -100 µM) (62,153). Therefore, they suggested that the α 2 δ subunit of Ca 2+ channels is the therapeutic action target of gabapentin.…”

Cellular and Behavioral Interactions of Gabapentin with Alcohol Dependence

“…Gabapentin also decreases monoaminergic synaptic transmission in rat hippocampus and neocortex by selectively inhibiting Ca 2ϩ influx through voltage-operated Ca 2ϩ channels (VOCCs) (Fink et al, 2000;Dooley et al, 2002;van Hooft et al, 2002). In addition, gabapentin is an agonist for the endogenously expressed GABA B gb1a-gb2 heteromers coupled to inhibition of VOCCs in intermediate pituitary melanotrope cell lines and in hippocampal neurons Ng et al, 2001;van Hooft et al, 2002).…”