AMPA　receptor　mediates　the　fast　excitatory　synaptic　transmission　in　the　central　nervous　system,　and　it　is　activated　by　the　binding　of　glutamate　that　results　in　the　opening　of　the　transmembrane　ion　channel.　In　the　present　work,　the　thermodynamic　method　developed　by　our　group　was　improved　and　then　applied　to　identify　the　functionally　key　residues　that　regulate　the　glutamate-binding　affinity　of　AMPA　receptor.　In　our　method,　the　key　residues　are　identified　as　those　whose　perturbation　largely　changes　the　ligand　binding　free　energy　of　the　protein.　It　is　found　that　besides　the　ligand　binding　sites,　other　residues　distant　from　the　binding　cleft　can　also　influence　the　glutamate　binding　affinity　through　a　long-range　allosteric　regulation.　These　allosteric　sites　include　the　hinge　region　of　the　ligand　binding　cleft,　the　dimer　interface　of　the　ligand　binding　domain,　the　linkers　between　the　ligand　binding　domain　and　the　transmembrane　domain,　and　the　interface　between　the　N-terminal　domain　and　the　ligand　binding　domain.　Our　calculation　results　are　consistent　with　the　available　experimental　data.　The　results　are　helpful　for　our　understanding　of　the　mechanism　of　long-range　allosteric　communication　in　the　AMPA　receptor　and　the　mechanism　of　channel　opening　triggered　by　glutamate　binding.