Nanoscale Mobility of the Apo State and TARP Stoichiometry Dictate the Gating Behavior of Alternatively Spliced AMPA Receptors.
Dawe, G Brent
Kadir, Md Fahim
Alexander, Ryan PD
Santander, Eduardo A
Aurousseau, Mark RP
Barrera, Nelson P
Kastrup, Jette S
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Dawe, G. B., Kadir, M. F., Venskutonytė, R., Perozzo, A. M., Yan, Y., Alexander, R. P., Navarrete, C., et al. (2019). Nanoscale Mobility of the Apo State and TARP Stoichiometry Dictate the Gating Behavior of Alternatively Spliced AMPA Receptors.. Neuron, 102 (5), 976-992.e5. https://doi.org/10.1016/j.neuron.2019.03.046
Neurotransmitter-gated ion-channels are allosteric proteins that switch on and off in response to agonist binding. Most studies have focused on the agonist-bound, activated channel whilst assigning a lesser role to the apo or resting state. Here, we show that nanoscale mobility of resting AMPA-type ionotropic glutamate receptors (AMPARs) predetermines responsiveness to neurotransmitter, allosteric anions and auxiliary TARP subunits. Mobility at rest is regulated by alternative splicing of the flip/flop cassette of the ligand-binding domain which controls motions in the distant AMPAR amino-terminal domain (NTD). Flip variants promote moderate NTD movement which establishes slower channel desensitization and robust regulation by anions and auxiliary subunits. In contrast, greater NTD mobility imparted by the flop cassette acts as a master-switch to override allosteric regulation. In AMPAR heteromers, TARP stoichiometry further modifies these actions of the flip/flop cassette generating two functionally-distinct classes of partially- and fully-TARPed receptors typical of cerebellar stellate and Purkinje cells.
Cerebellum, Purkinje Cells, Animals, Humans, Mice, Membrane Proteins, Receptors, AMPA, Protein Isoforms, Cryoelectron Microscopy, Microscopy, Atomic Force, Crystallography, X-Ray, Patch-Clamp Techniques, Ion Channel Gating, Alternative Splicing, Allosteric Regulation, Allosteric Site, Protein Structure, Quaternary, Protein Structure, Tertiary, HEK293 Cells, Protein Domains
External DOI: https://doi.org/10.1016/j.neuron.2019.03.046
This record's URL: https://www.repository.cam.ac.uk/handle/1810/291776
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Licence URL: https://creativecommons.org/licenses/by-nc-nd/4.0/