GABA_B receptor attenuation of GABA_A 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_B receptor can suppress the ionotropic GABA_A receptor current, in both the in vitro mouse retina and in human amygdala membrane fractions. Expression of amygdala membrane microdomains in Xenopus oocytes by microtransplantation produced functional ionotropic and metabotropic GABA receptors. Most GABA_A receptors had properties of α-subunit containing receptors, with ~5% having ρ-subunit properties. Only GABA_A receptors with α-subunit-like properties were regulated by GABA_B receptors. In mouse retinal ganglion cells, where only α-subunit-containing GABA_A receptors are expressed, GABA_B receptors suppressed GABA_A receptor currents. This suppression was blocked by GABA_B receptor antagonists, G-protein inhibitors, and GABA_B receptor antibodies. Based on the kinetic differences between metabotropic and ionotropic receptors, their interaction would suppress repeated, rapid GABAergic inhibition.