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Cell Rep. 2017 Aug 1;20(5):1123-1135. doi: 10.1016/j.celrep.2017.07.014.

Dual Effects of TARP γ-2 on Glutamate Efficacy Can Account for AMPA Receptor Autoinactivation.

Author information

1
Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.
2
Center for Membrane Biology, Department of Biochemistry and Molecular Biology, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
3
Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, UK. Electronic address: m.farrant@ucl.ac.uk.
4
Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, UK. Electronic address: s.cull-candy@ucl.ac.uk.

Abstract

Fast excitatory transmission in the CNS is mediated mainly by AMPA-type glutamate receptors (AMPARs) associated with transmembrane AMPAR regulatory proteins (TARPs). At the high glutamate concentrations typically seen during synaptic transmission, TARPs slow receptor desensitization and enhance mean channel conductance. However, their influence on channels gated by low glutamate concentrations, as encountered during delayed transmitter clearance or synaptic spillover, is poorly understood. We report here that TARP γ-2 reduces the ability of low glutamate concentrations to cause AMPAR desensitization and enhances channel gating at low glutamate occupancy. Simulations show that, by shifting the balance between AMPAR activation and desensitization, TARPs can markedly facilitate the transduction of spillover-mediated synaptic signaling. Furthermore, the dual effects of TARPs can account for biphasic steady-state glutamate concentration-response curves-a phenomenon termed "autoinactivation," previously thought to reflect desensitization-mediated AMPAR/TARP dissociation.

KEYWORDS:

EPSC; GluA1; cerebellar granule cell; diffusion model; kinetic model; short-term plasticity; single-channel; spillover; subconductance; synaptic

PMID:
28768197
PMCID:
PMC5554777
DOI:
10.1016/j.celrep.2017.07.014
[Indexed for MEDLINE]
Free PMC Article

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