A Venus flytrap mechanism for activation and desensitization of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors

Desensitization of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) subtype of glutamate receptor channels is an important process shaping the time course of synaptic excitation. Upon desensitization, the receptor channel closes and the agonist affinity increases. So far, the nature of the structural rearrangements leading to these events was unknown. On the basis of the structural homology of the ligand binding domains of AMPA receptors and of the bilobated bacterial periplasmic proteins, we now show that agonist interaction with one lobe of the GluR1 subunit of homomeric AMPA receptors controls channel activation while additional interactions with the other lobe cause channel desensitization. Accordingly, we suggest that the transition of the AMPA receptor channel to the desensitized state involves the agonist-mediated stabilization of the closed lobe conformation of its binding domain and is a process akin to that used by the venus flytrap.