Ionotropic glutamate receptors (iGluRs) are cation channels that mediate signal transmission in the central nervous system by depolarizing the postdynaptic membrane in response to L-glutamate release from the presynaptic neuron. GluA2 is a subunit of AMPA, a major subtypes of iGluRs, which harbors a modular architecture composed of an amino-terminal domain (ATD), angonist-recognizing ligand-binding domain (LBD), a transmembrane domain (TMD) that forms the ion channel pore, and intracellular carboxyl-terminal domains. To understand the ion channel activation mechanism, many efforts have been dedicated to obtain the structures of GluA2 in various functional states. While ATD, LBD structures in the close and open states have been obtained through x-ray and cryo-EM, the TMD structure is only available in the close state because the open state TMD is difficult to capture with crystallography and its cryo-EM maps are low in resolution. The Low resolution cryo-EM maps of GluA2 in the close, open, and desensitized states have been obtained, which opens a window to investigate the structural mechanism of the ion channel activation. MapSGLD is a method to determine molecular structures from low resolution maps by utilizing structural information embedded in the force field. Through MapSGLD simulations with the low resolution maps of GluA2 in the close, open, and desensitized states, we determined the structures of GluA2 in the corresponding states. The structures show that LBD clamshell is open in the close state and closed in the open and desensitized states. The TMD ion pore is closed in the close and desensitized states but open in the open state. We experimented with MapSGLD simulations using various portions of the cryo-EM maps and identified the structural mechanism to activate the ion channel.

Glutamate receptor ion channel activation mechanism revealed by computer experiment

253rd National Meeting (2017)

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