Nanoscale Mobility of the Apo State and TARP Stoichiometry Dictate the Gating Behavior of Alternatively Spliced AMPA Receptors.

Autor:	Dawe GB; Integrated Program in Neuroscience, McGill University, Montréal, QC H3A 2B4, Canada; Department of Pharmacology and Therapeutics, McGill University, Montréal, QC H3G 1Y6, Canada., Kadir MF; Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, UK., Venskutonytė R; Department of Drug Design and Pharmacology, University of Copenhagen, 2100 Copenhagen, Denmark., Perozzo AM; Integrated Program in Neuroscience, McGill University, Montréal, QC H3A 2B4, Canada; Department of Pharmacology and Therapeutics, McGill University, Montréal, QC H3G 1Y6, Canada., Yan Y; Integrated Program in Neuroscience, McGill University, Montréal, QC H3A 2B4, Canada; Department of Pharmacology and Therapeutics, McGill University, Montréal, QC H3G 1Y6, Canada., Alexander RPD; Integrated Program in Neuroscience, McGill University, Montréal, QC H3A 2B4, Canada; Department of Pharmacology and Therapeutics, McGill University, Montréal, QC H3G 1Y6, Canada., Navarrete C; Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, UK; Department of Physiology, Pontificia Universidad Católica de Chile, 8331150 Santiago, Chile., Santander EA; Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, UK., Arsenault M; Department of Pharmacology and Therapeutics, McGill University, Montréal, QC H3G 1Y6, Canada., Fuentes C; Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, UK; Department of Physiology, Pontificia Universidad Católica de Chile, 8331150 Santiago, Chile., Aurousseau MRP; Department of Pharmacology and Therapeutics, McGill University, Montréal, QC H3G 1Y6, Canada., Frydenvang K; Department of Drug Design and Pharmacology, University of Copenhagen, 2100 Copenhagen, Denmark., Barrera NP; Department of Physiology, Pontificia Universidad Católica de Chile, 8331150 Santiago, Chile., Kastrup JS; Department of Drug Design and Pharmacology, University of Copenhagen, 2100 Copenhagen, Denmark., Edwardson JM; Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, UK., Bowie D; Department of Pharmacology and Therapeutics, McGill University, Montréal, QC H3G 1Y6, Canada. Electronic address: derek.bowie@mcgill.ca.
Jazyk:	angličtina
Zdroj:	Neuron [Neuron] 2019 Jun 05; Vol. 102 (5), pp. 976-992.e5. Date of Electronic Publication: 2019 Apr 30.
DOI:	10.1016/j.neuron.2019.03.046
Abstrakt:	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. (Copyright © 2019 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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