Abstract
γ-aminobutyric acid type A receptors (GABAARs) are the major mediators of synaptic inhibition in the brain. Aberrant GABAAR activity or regulation is observed in various neurodevelopmental disorders, neurodegenerative diseases and mental illnesses, including epilepsy, Alzheimer’s and schizophrenia. Benzodiazepines, anesthetics and other pharmaceutics targeting these receptors find broad clinical use, but their inherent lack of receptor subtype specificity causes unavoidable side effects, raising a need for new or adjuvant medications. In this review article, we introduce a new strategy to modulate GABAeric signaling: targeting the intracellular protein interactors of GABAARs. Of special interest are scaffolding, anchoring and supporting proteins that display high GABAAR subtype specificity. Recent efforts to target gephyrin, the major intracellular integrator of GABAergic signaling, confirm that GABAAR-associated proteins can be successfully targeted through diverse molecules, including recombinant proteins, intrabodies, peptide-based probes and small molecules. Small-molecule artemisinins and peptides derived from endogenous interactors, that specifically target the universal receptor binding site of gephyrin, acutely affect synaptic GABAAR numbers and clustering, modifying neuronal transmission. Interference with GABAAR trafficking provides another way to modulate inhibitory signaling. Peptides blocking the binding site of GABAAR to AP2 increase the surface concentration of GABAAR clusters and enhance GABAergic signaling. Engineering of gephyrin binding peptides delivered superior means to interrogate neuronal structure and function. Fluorescent peptides, designed from gephyrin binders, enable live neuronal staining and visualization of gephyrin in the post synaptic sites with submicron resolution. We anticipate that in the future, novel fluorescent probes, with improved size and binding efficiency, may find wide application in super resolution microscopy studies, enlightening the nanoscale architecture of the inhibitory synapse. Broader studies on GABAAR accessory proteins and the identification of the exact molecular binding interfaces and affinities will advance the development of novel GABAAR modulators and following in vivo studies will reveal their clinical potential as adjuvant or stand-alone drugs.
Highlights
Dysfunctional GABAAR-Associated Proteins γ-aminobutyric acid type A receptors (GABAARs) are involved in the pathogenesis of neurodevelopmental disorders (Ali Rodriguez et al, 2018), schizophrenia, postpartum depression (Mody, 2019), epilepsy (Palma et al, 2017; Hines et al, 2018), Alzheimer’s disease (Govindpani et al, 2017), autism (Vien et al, 2015) and stroke (Darmani et al, 2016; Wang et al, 2018)
Modulators of GABAAR activity find broad clinical use as anesthetics (Propofol; Olsen, 2018), anticonvulsants (Gabapentin) or as hypnotics, musclerelaxants and anxiolytics (Clonazepam, Diazepam), and new experimental medicines are developed. Wider application of these classical GABAAR modulators is limited by their lack of receptor subtype specificity, due to the fundamental structural and functional constraints: pharmacologically exploited sites are small hydrophobic pockets with high subunit sequence homology located at the folded extracellular domain (ECD) and transmembrane domains (TMDs) of the ion channels (Figure 1; Miller et al, 2017; Kasaragod and Schindelin, 2018; Masiulis et al, 2019)
The large number of post-synaptic candidate proteins that directly or indirectly associate with GABAARs is still increasing (Krueger-Burg et al, 2017), with functional studies exploring some of their physiological roles and organization (Uezu et al, 2016; Lu et al, 2017), yet, the specific molecular details of these interactions remain largely unknown
Summary
Γ-aminobutyric acid type A receptors (GABAARs) are the principal mediators of phasic and tonic inhibition in the human brain, being a vital part of the molecular machinery that creates cognition, behavior, and consciousness (Fritschy and Panzanelli, 2014). Dysfunctional GABAARs are involved in the pathogenesis of neurodevelopmental disorders (Ali Rodriguez et al, 2018), schizophrenia (de Jonge et al, 2017), postpartum depression (Mody, 2019), epilepsy (Palma et al, 2017; Hines et al, 2018), Alzheimer’s disease (Govindpani et al, 2017), autism (Vien et al, 2015) and stroke (Darmani et al, 2016; Wang et al, 2018) These receptors belong to the pentameric ligand-gated ion channels harboring an extracellular domain (ECD), followed by four helical transmembrane domains (TMDs) and loops connecting these helices. We hypothesize that the identification of the exact molecular binding interfaces and binding affinities of known and newly identified GABAAR associated proteins will greatly expand our basic understanding of CNS function, and provide new pharmaceutical opportunities
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