Influence of GABAAr monoliganded states on GABAergic responses

Abstract

To reach the open state, the GABAA receptor (GABAAR) is assumed to bind two agonist molecules. Although it is currently believed that GABAAR could also operate in the monoliganded state, the gating properties of singly bound GABAAR are poorly understood and their physiological role is still obscure. In the present study, we characterize for the first time the gating properties of singly bound GABAARs by using a mutagenesis approach and we propose that monoliganded GABAAR contribute in shaping synaptic responses. At saturating GABA concentrations, currents mediated by recombinant GABAARs with a single functional binding site display slow onset, fast deactivation kinetics, and slow rate of desensitization-resensitization. GABAARs with two binding sites activated by brief pulses of subsaturating GABA concentrations (in the range of the GABA concentration profile in the synaptic cleft) could also mediate fast deactivating currents, displaying deactivation kinetics similar to those mediated by GABAARs with a single functional binding site. Model simulations of receptors activated by realistic synaptic GABA waves revealed that a considerable proportion of GABAA receptors open in the monoliganded state during synaptic transmission, therefore contributing in shaping IPSCs. Copyright©2011 the authors.