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

• Published in: Cell reports (Cambridge) Vol. 20; no. 5; pp. 1123 - 1135
• Main Authors: Coombs, Ian D., MacLean, David M., Jayaraman, Vasanthi, Farrant, Mark, Cull-Candy, Stuart G.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2017; Cell Press; Elsevier
• Subjects: Calcium Channels - genetics; Calcium Channels - metabolism; cerebellar granule cell; diffusion model; EPSC; GluA1; Glutamic Acid - genetics; Glutamic Acid - metabolism; HEK293 Cells; Humans; kinetic model; Receptors, AMPA - genetics; Receptors, AMPA - metabolism; short-term plasticity; single-channel; spillover; subconductance; synaptic; spillover; diffusion model; kinetic model; subconductance; single-channel; GluA1; EPSC; synaptic; short-term plasticity; cerebellar granule cell
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2017.07.014

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. [Display omitted] •TARP γ-2 reduces desensitization and enhances the gating of singly liganded AMPARs•This accounts for biphasic steady-state dose-response curves (autoinactivation)•The effects of γ-2 are predicted to enhance synaptic spillover currents•Desensitization does not lead to functional dissociation of the AMPAR/TARP complex 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.