Agonist pharmacology ofneonatal andadult glycine receptor oasubunits: identification ofaminoacid residues involved intaurine activation

furHirnforschung, Deutschordenstrasse 46,6000Frankfurt amMain71,FRG Communicated byH.Betz Theinhibitory glycine receptor (GlyR) isapentameric chloride channel protein whichmediates postsynaptic inhibition inthemammalian central nervous system. In spinal cord, different GlyRisoforms originate fromthe sequential expression ofdevelopmentally regulated variants oftheligand binding asubunit. Here, neonatal a2andadult alsubunits areshowntogenerate GlyRs withdistinct agonist activation profiles uponheterologous expression inXenopus oocytes. Whereasalreceptors areefficiently gated by,B-alanine andtaurine, a2GlyRs showonly alowrelative response tothese agonists, which alsodisplay areduced sensitivity toinhibition bythe glycinergic antagonist strychnine. Construction ofan a2/al subunit chimera andsite-directed mutagenesis of theextracellular region ofthealsequence identified aminoacidpositions 111and212asimportant determinants oftaurine activation. Ourresults indicate the existence ofdistinct subsites foragonists onalanda2 GlyRs andsuggest that theligand binding pocket ofthese receptor proteins isformed fromdiscontinuous domains