TY  - JOUR
A1  - Kasaragod, Vikram Babu
A1  - Schindelin, Hermann
T1  - Structure of Heteropentameric GABAA Receptors and Receptor-Anchoring Properties of Gephyrin
T2  - Frontiers in Molecular Neuroscience
N2  - γ-Aminobutyric acid type A receptors (GABAARs) mediate the majority of fast synaptic inhibition in the central nervous system (CNS). GABAARs belong to the Cys-loop superfamily of pentameric ligand-gated ion channels (pLGIC) and are assembled from 19 different subunits. As dysfunctional GABAergic neurotransmission manifests itself in neurodevelopmental disorders including epilepsy and anxiety, GABAARs are key drug targets. The majority of synaptic GABAARs are anchored at the inhibitory postsynaptic membrane by the principal scaffolding protein gephyrin, which acts as the central organizer in maintaining the architecture of the inhibitory postsynaptic density (iPSD). This interaction is mediated by the long intracellular loop located in between transmembrane helices 3 and 4 (M3–M4 loop) of the receptors and a universal receptor-binding pocket residing in the C-terminal domain of gephyrin. In 2014, the crystal structure of the β3-homopentameric GABAAR provided crucial information regarding the architecture of the receptor; however, an understanding of the structure and assembly of heteropentameric receptors at the atomic level was lacking. This review article will highlight recent advances in understanding the structure of heteropentameric synaptic GABAARs and how these structures have provided fundamental insights into the assembly of these multi-subunit receptors as well as their modulation by diverse ligands including the physiological agonist GABA. We will further discuss the role of gephyrin in the anchoring of synaptic GABAARs and glycine receptors (GlyRs), which are crucial for maintaining the architecture of the iPSD. Finally, we will also summarize how anti-malarial artemisinin drugs modulate gephyrin-mediated inhibitory neurotransmission.
KW  - GABAA
KW  - gephyrin
KW  - diazepam
KW  - GABA
KW  - PIP2
KW  - artemisinin
KW  - Cryo-EM
KW  - inhibitory neurotransmission
Y1  - 2019
UR  - https://opus.bibliothek.uni-wuerzburg.de/frontdoor/index/index/docId/18930
UR  - https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-189308
SN  - 1662-5099
VL  - 12
ER  -