8c2i
Transmembrane domain of resting state homomeric GluA1 AMPA receptor in complex with TARP gamma 3
Structural highlights
FunctionGRIA1_RAT Ionotropic glutamate receptor. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. Binding of the excitatory neurotransmitter L-glutamate induces a conformation change, leading to the opening of the cation channel, and thereby converts the chemical signal to an electrical impulse. The receptor then desensitizes rapidly and enters a transient inactive state, characterized by the presence of bound agonist. In the presence of CACNG4 or CACNG7 or CACNG8, shows resensitization which is characterized by a delayed accumulation of current flux upon continued application of glutamate.[1] [2] Publication Abstract from PubMedAMPA glutamate receptors (AMPARs), the primary mediators of excitatory neurotransmission in the brain, are either GluA2 subunit-containing and thus Ca(2+)-impermeable, or GluA2-lacking and Ca(2+)-permeable(1). Despite their prominent expression throughout interneurons and glia, their role in long-term potentiation and their involvement in a range of neuropathologies(2), structural information for GluA2-lacking receptors is currently absent. Here we determine and characterize cryo-electron microscopy structures of the GluA1 homotetramer, fully occupied with TARPgamma3 auxiliary subunits (GluA1/gamma3). The gating core of both resting and open-state GluA1/gamma3 closely resembles GluA2-containing receptors. However, the sequence-diverse N-terminal domains (NTDs) give rise to a highly mobile assembly, enabling domain swapping and subunit re-alignments in the ligand-binding domain tier that are pronounced in desensitized states. These transitions underlie the unique kinetic properties of GluA1. A GluA2 mutant (F231A) increasing NTD dynamics phenocopies this behaviour, and exhibits reduced synaptic responses, reflecting the anchoring function of the AMPAR NTD at the synapse. Together, this work underscores how the subunit-diverse NTDs determine subunit arrangement, gating properties and ultimately synaptic signalling efficiency among AMPAR subtypes. Structural mobility tunes signalling of the GluA1 AMPA glutamate receptor.,Zhang D, Ivica J, Krieger JM, Ho H, Yamashita K, Stockwell I, Baradaran R, Cais O, Greger IH Nature. 2023 Sep;621(7980):877-882. doi: 10.1038/s41586-023-06528-0. Epub 2023 , Sep 13. PMID:37704721[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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