Abstract:
Ionotropic glutamate receptors (iGluRs) mediate fast excitatory synaptic transmission in the central nervous system. Upon agonist binding, an
iGluR opens to allow the flow of cations and subsequently enters into a desensitized state. It remains unclear how agonist binding to the
ligand-binding domain (LBD) is transmitted to the transmembrane domain (TMD) for channel activation and desensitization. Here we report
molecular dynamics simulations of an AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)-subtype iGluR in explicit water and
membrane. Channel opening and closing were observed in simulations of the activation and desensitization processes, respectively. The motions
of the LBD–TMD linkers along the central axis of the receptor and in the lateral plane contributed cooperatively to channel opening and closing.
The detailed mechanism of channel activation and desensitization suggested by the simulations here is consistent with existing data and may
serve as a guide for new experiments and for the design of pharmacological.