A Role for Loop F in Modulating GABA Binding Affinity in the GABAA Receptor

GABA A receptor target of tetramethylenedisulfotetramine

“…Thus, a β 3 homopentamer 1′V→T or 2′ A→S mutant (similar to the α 1 or γ 2 residues) may show increased affinity for TETS. 36 Cl uptake in membrane vesicles of the cerebral cortex (20,32). Type A compounds include EBOB and many insecticides with large substituents or extended structures, and the type B set includes TETS, TBPS, TBPO, and other small compact molecules, some of very high i.p.…”

“…The GABA A R α 1 β 2 γ 2 homology model was built with a GluCl template (PDB ID code 3RHW) (48) using previously published protocols (36,37). Small molecules were parameterized with the PRODRG server (49) and docked into the pore using VinaLC (50).…”

Respiratory rhythm generation and pattern formation: oscillators and network mechanisms

“…GABAB receptors are diffusely distributed synaptodendritically, somatically, and axonally, localizing to presynaptic terminals (Delaney and Crane, 2016;Orts-Del'Immagine and Pugh, 2018), postsynaptic membranes (Chalifoux and Carter, 2011;Crunelli and Leresche, 1991;Gonzalez-Burgos, 2010;Mouginot and Gähwiler, 1996;Serrats et al, 2017), or extrasynaptic (Pham et al, 1998) zones. GABAB receptors located within synaptic zones are generally of low affinity (Carpenter et al, 2012), appropriately suited given the extremely high concentration of GABA generated by synaptovesicular fusion and release of neurotransmitter within the confines of the synaptic cleft, contrasted with the very high ligand binding affinity demonstrated by GABA receptors located in extrasynaptic zones (Barolet et al, 1985;Gonzalez-Burgos, 2010). This represents a necessary and wise construct of nature conferring modulatory influence upon extrasynaptic signaling given the significantly lower amounts of GABA diffusing to these regions (personal communication, Emer-itus Professor Dr. Vitaliy Marchenko).…”

Orthosteric and benzodiazepine cavities of the α1β2γ2 GABAA receptor: insights from experimentally validated in silico methods

“…ProSa z-score (Wiederstein & Sippl, 2007),Q-mean score (Benkert, Tosatto, & Schomburg, 2008) and PROCHECK (Laskowski, MacArthur, Moss, & Thornton, 1993) results were also taken into account in the selection process. These evaluation webservers have been extensively applied in several works concerning homology modelling (Carpenter et al, 2012;Roy & Mukherjee, 2017). Moreover, the top 20 models were carefully visually inspected to detect abnormalities.…”

“…Furthermore, there are other non-benzodiazepine ligands of this site, which include the imidazopyridine Zolpidem and the cyclopyrrolone Eszopiclone (S-zopiclone) ( Figure 3). Acetylcholine-binding proteins and non-eukaryotic receptors such as ELIC (Erwinia ligand-gated ion channel), GLIC (Gloeobacter ligand-gated ion channel) and invertebrate Glutamate receptors have been extensively used in the past as templates to model mammalian Cys-Loop receptors (Berezhnoy, Gibbs, & Farb, 2009;Bertaccini, Yoluk, Lindahl, & Trudell, 2013;Carpenter, Lau, & Lightstone, 2012;Carpenter & Lightstone, 2016;Cromer, Morton, & Parker, 2002;Ernst, Brauchart, Boresch, & Sieghart, 2003;Hénin, Salari, Murlidaran, & Brannigan, 2014;Puthenkalam et al, 2016;Sander et al, 2011;Thompson, Lester, & Lummis, 2010;Xie, Sha, Wang, & Cheng, 2013). However, in 2014 the first 3D structure of a GABA A receptor was published by Miller and Aricescu .…”