The GlyR Extracellular β8-β9 Loop - A Functional Determinant of Agonist Potency.

摘要: Ligand-binding of Cys-loop receptors results in rearrangements extracellular loop structures which are further translated into the tilting membrane spanning helices, and finally opening ion channels. The cryo-EM structure homopentameric 1 glycine receptor (GlyR) demonstrated an involvement β8-β9 transition from ligand-bound to open channel state. Recently, we identified a functional role novel startle disease mouse model shaky. mutation residue GlyRα1Q177 lysine present shaky mice resulted reduced potency, synaptic expression, disrupted hydrogen network at structural level around position GlyRα1Q177. Here, investigated amino acid volume, side chain length, charge Q177 get deeper insights loop. We used combined approach vitro expression analysis, electrophysiological recordings, GlyR modeling describe for function. variants do not disturb transport cellular surface transfected cells, neither homomeric nor heteromeric configurations. EC50 values were increased all comparison wild type. largest decrease potency was observed variant GlyRα1Q177R. Potencies partial agonists -alanine taurine also reduced. Our data supported by homology modeling. GlyRα1Q177R does form bonds with surrounding similar substitution basic mutant Among mutants, neutral exchange glutamine asparagine as well introduction closely related glutamic preserve bond network. Introduction acids small chains or larger volume loss their neighboring residues. is thus important determinant inhibitory receptor.