GABA Receptor Attenuation of GABA Currents in Neurons of the Mammalian Central Nervous System

Ionotropic receptors are tightly regulated by second messenger systems and are often present along with their metabotropic counterparts on a neuron's plasma membrane. This leads to the hypothesis that the two receptor subtypes can interact, and indeed this has been observed in excitatory glutamate and inhibitory GABA receptors. In both systems the metabotropic pathway augments the ionotropic receptor response. However, we have found that the metabotropic GABA receptor can suppress the ionotropic GABA receptor current, in both the in vitro mouse retina and in human amygdala membrane fractions. Expression of amygdala membrane microdomains in oocytes by microtransplantation produced functional ionotropic and metabotropic GABA receptors. Most GABA receptors had properties of -subunit containing receptors, with ~5% having -subunit properties. Only GABA receptors with -subunit-like properties were regulated by GABA receptors. In mouse retinal ganglion cells, where only -subunit-containing GABA receptors are expressed, GABA receptors suppressed GABA receptor currents. This suppression was blocked by GABA receptor antagonists, G-protein inhibitors, and GABA receptor antibodies. Based on the kinetic differences between metabotropic and ionotropic receptors, their interaction would suppress repeated, rapid GABAergic inhibition.