Regulation of inhibitory synaptic transmission by a conserved atypical interaction of GABA_A receptor β- and γ-subunits with the clathrin AP2 adaptor

The number of surface and synaptic GABA_A receptors is an important determinant of inhibitory synapse strength. Surface receptor number is in part controlled by removal of receptors from the membrane by interaction with the clathrin adaptor AP2. Here we demonstrate that there are two binding sites for AP2 in the γ2-subunit: a Yxxφ{symbol} type motif specific to γ2-subunits and a basic patch AP2 binding motif, that is also found in GABA_A receptor β-subunits. Blocking GABA_A receptor-AP2 interactions using a peptide that inhibits AP2 binding to GABA_A receptors via the conserved basic patch mechanism increases synaptic responses within minutes, whereas simultaneously blocking both binding mechanisms has an additive effect. These data suggest that multiple AP2 internalization signals control the levels of surface and synaptic GABA_A receptors to regulate synaptic inhibition.