Nanoscale Mobility of the Apo State and TARP Stoichiometry Dictate the Gating Behavior of Alternatively Spliced AMPA Receptors
| Autor: | Dawe, G Brent, Kadir, Md Fahim, Venskutonytė, Raminta, Perozzo, Amanda M, Yan, Yuhao, Alexander, Ryan PD, Navarrete, Camilo, Santander, Eduardo A, Arsenault, Marika, Fuentes, Christian, Aurousseau, Mark RP, Frydenvang, Karla, Barrera, Nelson P, Kastrup, Jette S, Edwardson, J Michael, Bowie, Derek |
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| Přispěvatelé: | Perozzo, Amanda M [0000-0001-9681-3548], Bowie, Derek [0000-0001-9491-8768], Apollo - University of Cambridge Repository |
| Rok vydání: | 2019 |
| Předmět: |
Patch-Clamp Techniques
channel gating Crystallography X-Ray Microscopy Atomic Force patch clamp ionotropic glutamate receptor alternative splicing Mice Purkinje Cells Allosteric Regulation Protein Domains synapse Cerebellum Animals Humans Protein Isoforms protein conformations Receptors AMPA Protein Structure Quaternary X-ray crystallography atomic force microscopy Cryoelectron Microscopy Membrane Proteins electrophysiology Protein Structure Tertiary HEK293 Cells ion channel Ion Channel Gating Allosteric Site |
| DOI: | 10.17863/cam.38936 |
| Popis: | 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 while assigning a lesser role to the apo or resting state. Here, we show that nanoscale mobility of resting α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type ionotropic glutamate receptors (AMPA receptors) predetermines responsiveness to neurotransmitter, allosteric anions and TARP auxiliary 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 AMPA receptor N-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 AMPA receptor 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. |
| Databáze: | OpenAIRE |
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