Influence of GABAAR Monoliganded States on GABAergic Responses.

To reach the open state, the GABAAreceptor (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 GABAAreceptors open in the monoliganded state during synaptic transmission, therefore contributing in shaping IPSCs.</jats:p

GABAA receptor membrane trafficking regulates spine maturity

GABAA receptors (GABAARs), the principal sites of synaptic inhibition in the brain, are dynamic entities on the neuronal cell surface, but the role their membrane trafficking plays in shaping neuronal activity remains obscure. Here, we examined this by using mutant receptor β3 subunits (β3S408/9A), which have reduced binding to the clathrin adaptor protein-2, a critical regulator of GABAAR endocytosis. Neurons expressing β3S408/9A subunits exhibited increases in the number and size of inhibitory synapses, together with enhanced inhibitory synaptic transmission due to reduced GABAAR endocytosis. Furthermore, neurons expressing β3S408/9A subunits had deficits in the number of mature spines and reduced accumulation of postsynaptic density protein-95 at excitatory synapses. This deficit in spine maturity was reversed by pharmacological blockade of GABAARs. Therefore, regulating the efficacy of synaptic inhibition by modulating GABAAR membrane trafficking may play a critical role in regulating spine maturity with significant implications for synaptic plasticity together with behavior

Molecular architecture of potassium chloride co-transporter KCC2

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