Modulation of receptor traffick- ing is critical for controlling neurotransmission. A γ2(R43Q) point mutation on GABAA receptor subunit is linked to epilepsy in human. We recently analyzed the effect of this amino-acid substitution on GABAA receptor traf- ficking and showed that this muta- tion as well as agonist application, both affecting GABA receptor extracellular cytosis. By comparing homology models based on ligand gated ion channels in their active and resting states, we reveal that the γ2R43 domain is located in a loop that is affected by motion resulting from receptor activation. Taken together, these results suggest that endocytosis of GABAA receptors is linked to agonist induced conformational changes. We propose that ligand or modulator bind- ing is followed by a whole chain of inter- connections, including the intracellular domain, that may influence ligand-gated channel trafficking.