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

Abstract

Summary: 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. : AMPA receptors are regulated by accessory proteins, including TARP γ-2. Coombs et al. show how γ-2 can give rise to receptor behavior previously attributed to glutamate-induced dissociation of the AMPAR/TARP assembly. By favoring the gating of singly liganded receptors, γ-2 is predicted to facilitate synaptic signaling by low concentrations of glutamate. Keywords: GluA1, kinetic model, single-channel, subconductance, cerebellar granule cell, diffusion model, synaptic, EPSC, spillover, short-term plasticity