Functional regulation of GABAA receptors in nervous system pathologies

Abstract

Inhibitory neurotransmission is primarily governed by γ-aminobutyric acid (GABA) type A receptors (GABAARs). GABAARs are heteropentameric ligand-gated channels formed by the combination of 19 possible subunits. GABAAR subunits are subject to multiple types of regulation, impacting the localization, properties, and function of assembled receptors. GABAARs mediate both phasic (synaptic) and tonic (extrasynaptic) inhibition. While the regulatory mechanisms governing synaptic receptors have begun to be defined, little is known about the regulation of extrasynaptic receptors. We examine the contributions of GABAARs to the pathogenesis of neurodevelopmental disorders, schizophrenia, depression, epilepsy, and stroke, with particular focus on extrasynaptic GABAARs. We suggest that extrasynaptic GABAARs are attractive targets for the treatment of these disorders, and that research should be focused on delineating the mechanisms that regulate extrasynaptic GABAARs, promoting new therapeutic approaches.

Figure 1

Mechanisms regulating the accumulation of synaptic/phasic and extrasynaptic/tonic GABA_ARs. The basal GABA_A current represents a combination of phasic inhibitory currents in a background of extrasynaptic GABA_AR activation. Phasic GABA_AR currents (mIPSCs, left panel) arise from the release of GABA-containing vesicles from a presynaptic terminal directly opposed to receptors clustered at the corresponding postsynaptic specialization. In the case of tonic inhibition (right panel), low ambient concentrations of GABA (or other agonists such as taurine), result in tonic activation of high affinity extrasynaptic receptors. The tonic current can be measured by application of a specific GABA_A antagonist, which blocks both phasic and tonic channel activity, resulting in a shift of the holding current that can be interpreted as the tonic GABA_AR contribution. (Currents shown are schematics.) Both phasic and tonic forms of GABA_AR inhibition rely on the appropriate targeting/clustering and function of distinct classes of GABA_ARs containing α1–3,βx,γ2 and α4–6,βx,δ receptor subunits, respectively. Studies from multiple laboratories have begun to define the mechanisms regulating the accumulation of synaptic GABA_ARs. The scaffolding protein gephyrin has been indicated as a key player in localizing synaptic GABA_ARs. In the cytosol, gephyrin exists as a trimer and relies on cooperative interactions with collybistin and neuroligin2 for enrichment at the plasma membrane. The complex of gephyrin–collybistin–neuroligin2, via interaction with presynaptic neurexins, helps to align the postsynaptic specialization with presynaptic GABA-releasing terminals. The clustering of GABA_ARs in the postsynaptic specialization is facilitated by interaction of specific subunits (α1, α2, α3) with gephyrin. In contrast to synaptic receptors, the proteins interacting with, and regulating the clustering of extrasynaptic receptors are largely unknown. To this point, only radixin has been indicated to interact with the α5 subunit, which is known to be present at extrasynaptic sites.