AUTHOR=Kasaragod Vikram B. , Schindelin Hermann 

TITLE=Structure–Function Relationships of Glycine and GABAA Receptors and Their Interplay With the Scaffolding Protein Gephyrin

JOURNAL=Frontiers in Molecular Neuroscience

VOLUME=Volume 11 - 2018

YEAR=2018

URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2018.00317

DOI=10.3389/fnmol.2018.00317

ISSN=1662-5099

ABSTRACT=Glycine and gama-aminobutyric acid (GABA) are the major determinants of inhibition in the central
nervous system (CNS). These neurotransmitters target glycine and GABA(A) receptors, respectively,
which both belong to the Cys-loop superfamily of pentameric ligand-gated ion channels (pLICs).
Interactions of the neurotransmitters with the cognate receptors result in receptor opening and a
subsequent influx of chloride ions, which, in turn, leads to hyperpolarization of the membrane
potential, thus counteracting excitatory stimuli. The majority of glycine receptors and a significant
fraction of GABA(A) receptors (GABA(A)Rs) are recruited and anchored to the postsynaptic membrane
by the central scaffolding protein gephyrin. This ~93 kDa moonlighting protein is structurally
organized into an N-terminal G-domain (GephG) connected to a C-terminal E-domain (GephE) via a
long unstructured linker. Both inhibitory neurotransmitter receptors interact via a short peptide motif
located in the large cytoplasmic loop located in between transmembrane helices 3 and 4 (TM3-TM4)
of the receptors with a universal receptor-binding epitope residing in GephE. Gephyrin engages in
nearly identical interactions with the receptors at the N-terminal end of the peptide motif, and
receptor-specific interaction towards the C-terminal region of the peptide. In addition to its receptor-
anchoring function, gephyrin also interacts with a rather large collection of macromolecules
including different cytoskeletal elements, thus acting as central scaffold at inhibitory postsynaptic
specializations. Dysfunctions in receptor-mediated or gephyrin-mediated neurotransmission have been identified in various severe neurodevelopmental disorders. Although biochemical, cellular and
electrophysiological studies have helped to understand the physiological and pharmacological roles
of the receptors, recent atomic-resolution structures of the receptors have strengthened our
understanding of the receptors and their gating mechanisms. Besides that, multiple crystal structures
of GephE in complex with receptor-derived peptides have shed light into receptor clustering by
gephyrin at inhibitory postsynapses. This review will highlight recent biochemical and structural
insights into gephyrin and the GlyR-beta as well as GABA(A) receptors, which provide a deeper
understanding of the molecular machinery mediating inhibitory neurotransmission.