Abstract
SummaryFast 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.
Highlights
Glutamate receptors of the AMPA subtype (AMPARs) mediate fast excitatory signaling throughout the mammalian brain (Traynelis et al, 2010)
We examined the effect of transmembrane AMPAR regulatory proteins (TARPs) g-2 on the occupancy dependence of AMPAR gating and the concentration dependence of AMPAR desensitization
TARP g-2 Reduces Desensitization of AMPARs by Low Concentrations of Glutamate TARPs increase the potency of glutamate to activate AMPARs (Suzuki et al, 2008; Tomita et al, 2005), but their effects on the potency of glutamate to promote AMPAR desensitization have not been established
Summary
Glutamate receptors of the AMPA subtype (AMPARs) mediate fast excitatory signaling throughout the mammalian brain (Traynelis et al, 2010). Assembled receptors interact with up to four TARPs (Hastie et al, 2013; Kim et al, 2010; Shi et al, 2009), primarily through transmembrane contacts running the length of the pore-forming regions as well as through contacts with the ligand binding domain (Shaikh et al, 2016; Twomey et al, 2016; Zhao et al, 2016). AMPAR interactions with the TARP intracellular C-terminal domain, its first extracellular loop (Ex1), and the transmembrane (TM) regions can all modulate multiple receptor properties (Ben-Yaacov et al, 2017; Cais et al, 2014; Dawe et al, 2016; Soto et al, 2014; Tomita et al, 2005; Turetsky et al, 2005). Desensitization can be triggered by just a single LBD closure
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