Targeting GABAAR-Associated Proteins: New Modulators, Labels and Concepts

Abstract

γ-aminobutyric acid type A receptors (GABA A Rs) are the major mediators of synaptic inhibition in the brain. Aberrant GABA A R 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 GABA A Rs. Of special interest are scaffolding, anchoring and supporting proteins that display high GABA A R subtype specificity. Recent efforts to target gephyrin, the major intracellular integrator of GABAergic signaling, confirm that GABA A R-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 GABA A R numbers and clustering, modifying neuronal transmission. Interference with GABA A R trafficking provides another way to modulate inhibitory signaling. Peptides blocking the binding site of GABA A R to AP2 increase the surface concentration of GABA A R 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 GABA A R accessory proteins and the identification of the exact molecular binding interfaces and affinities will advance the development of novel GABA A R modulators and following in vivo studies will reveal their clinical potential as adjuvant or stand-alone drugs.

Looking for Novelty in an “Old” Receptor: Recent Advances Toward Our Understanding of GABAARs and Their Implications in Receptor Pharmacology

“…Although a majority of compounds have been developed that target the pore-forming subunits of GABA A Rs, recent advances in the field of GABA A R biology have illuminated that native GABA A R exist as a complex with other accessory proteins rather than in isolation ( Khayenko and Maric, 2019 ). Within the past decade ( Figure 1 ), novel transmembrane proteins have been discovered that associate with native GABA A Rs and have distinct effects on receptor trafficking, kinetics, and/or pharmacology (see Han et al, 2020 for an in-depth review).…”

“…In addition to GABA A R-associated scaffolds and molecular adaptor proteins ( Khayenko and Maric, 2019 ), newly identified transmembrane proteins that interact with GABA A Rs are additional targets that can potentially be exploited in drug development. In fact, transmembrane AMPAR regulatory proteins (TARPs), which are auxiliary subunits of AMPA receptors ( Ziff, 2007 ; Milstein and Nicoll, 2008 ), are currently being evaluated for the treatment of epilepsy and pain ( Maher et al, 2017 ).…”

Low-concentration sevoflurane inhalation in treating MK801-induced schizophrenia like disease in mice and a feasibility study of schizophrenia patients

“…Previous studies suggest the glutamatergic and GABAergic neurons and their neurotransmitter systems play crucial roles in the pathophysiology of schizophrenia 12 ; but, currently, there are no relevant new medications available for clinical use. GABA A receptors are heteropentameric structures assembled from a large family of subunits including two α (α1-6), two β (β1-3), and either one γ (γ1-3) or one δ subunit 15 .…”

“…γ-aminobutyric acid type A receptors (GABA A R) are a family of ligand-gated ion channels essential for the regulation of synaptic inhibition in the brain 10 . Aberrant GABA A R activities or dysregulation thereof are associated with various neurodevelopmental disorders, neurodegenerative diseases and psychiatric diseases, including autism, Alzheimer's, depression and schizophrenia 11,12 . With growing studies on γaminobutyric acid type A (GABA A ) receptors (GABA A R) accessory proteins and the molecules modulating receptor signaling in the central nervous system, targeting GABA A R and associated proteins might shed a light to novel therapeutic development for psychotic disorders.…”

Targeted delivery of paclitaxel by NL2 peptide‐functionalized on core‐shell LaVO4: Eu3@ poly (levodopa) luminescent nanoparticles

“…NL2 peptide (AEGEFIHNRYNRFFYWYGDPAK) is a tumor‐targeting peptide that was first synthesized by the T7 phage library A 24 . Also, previous studies have shown that NL2 peptide has good stability and tumor targeting activity with a specific diagnosis of HER2 tumor marker without toxicity 25,26 . Human epidermal growth factor receptor 2 (HER2) is known as a tumor marker that is overexpressed on more than 30% of breast cancers (HER2, c‐erbB2) B .…”