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

Fast excitatory transmission in the CNS is mediated mainly by AMPA-type glutamate receptors (AMPARs) associated with transmembrane AMPAR regulatory proteins At the high glutamate concentrations typically seen during synaptic transmission, 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 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, Tduanyu37s can markedly facilitate the transduction of spillover-mediated synaptic signaling. Furthermore, the dual effects of Tduanyu37s can account for biphasic steady-state glutamate concentration-response curves-a phenomenon termed "autoinactivation," previously thought to reflect desensitization-mediated dissociation.

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