The clustering of GABA(A) receptor subtypes at inhibitory synapses is facilitated via the direct binding of receptor alpha 2 subunits to gephyrin.

Classical benzodiazepine sensitive GABA(A) receptor subtypes, the major mediators of fast synaptic inhibition in the brain are heteropentamers that can be assembled from alpha1-3/5, beta1-3, and gamma2 subunits, but how neurons orchestrate their selective accumulation at synapses remains obscure. We have identified a 10 amino acid hydrophobic motif within the intracellular domain of the alpha2 subunit that regulates the accumulation of GABA(A) receptors at inhibitory synaptic sites on both axon initial segments and dendrites in a mechanism dependent on the inhibitory scaffold protein gephyrin. This motif was sufficient to target CD4 (cluster of differentiation molecule 4) molecules to inhibitory synapses, and was also critical in regulating the direct binding of alpha2 subunits to gephyrin in vitro. Our results thus reveal that the specific accumulation of GABA(A) receptor subtypes containing alpha2 subunits at inhibitory synapses is dependent on their ability to bind gephyrin.