GABAB receptor attenuation of GABAA currents in neurons of the mammalian central nervous system.

Wen Shen,Harris Ripps,Changlong Nan,Peter T Nelson,Malcolm M Slaughter

doi:10.14814/phy2.13129

Abstract

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 GABAB receptor can suppress the ionotropic GABAA 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 GABAA receptors had properties of α‐subunit containing receptors, with ~5% having ρ‐subunit properties. Only GABAA receptors with α‐subunit‐like properties were regulated by GABAB receptors. In mouse retinal ganglion cells, where only α‐subunit‐containing GABAA receptors are expressed, GABAB receptors suppressed GABAA receptor currents. This suppression was blocked by GABAB receptor antagonists, G‐protein inhibitors, and GABAB receptor antibodies. Based on the kinetic differences between metabotropic and ionotropic receptors, their interaction would suppress repeated, rapid GABAergic inhibition.

Highlights

GABA, the major inhibitory transmitter in brain, binds fastacting ionotropic GABAARs that function as ClÀ permeable heteropentameric ion channels
Interactions between GABA receptor subtypes. The findings, from both in vitro retina and transplanted amygdala membrane, are that the GABABR can suppress the inhibitory action of GABAARs
The results extend the original observation in bullfrog dorsal root ganglion (Xi et al 1997) to the mammalian central nervous system and indicate that this regulation may be a common feature at GABA synapses

Summary

Introduction

GABA, the major inhibitory transmitter in brain, binds fastacting ionotropic GABAARs that function as ClÀ permeable heteropentameric ion channels. GABA activates slower, metabotropic GABAB G-protein-coupled receptors (GPCRs) that regulate voltage-gated K+ and Ca2+ channels (Bowery et al 1980; Kaupmann et al 1998). As their activity influences many neural systems and behavioral states, the GABABR is a major target of therapeutic drugs for mental disorders and drugs of abuse (Bettler et al 2004). Both retina and amygdala express high levels of ionotropic and metabotropic GABA receptors (Li et al 1996). GABAergic transmission is crucial for the low firing rate and strong inhibitory tone in amygdala and projection neurons that target the thalamus and hypothalamus (Barnard et al 1998; Lang and Pare 1998; Quirk and Gehlert 2003) and have been linked to emotional behavior, such as anxiety (Lehner et al 2010)

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