Autoinactivation of Neuronal AMPA Receptors via Glutamate-Regulated TARP Interaction

• Published in: Neuron (Cambridge, Mass.) Vol. 61; no. 1; pp. 101 - 112
• Main Authors: Morimoto-Tomita, Megumi, Zhang, Wei, Straub, Christoph, Cho, Chang-Hoon, Kim, Kwang S., Howe, James R., Tomita, Susumu
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.01.2009; Elsevier Limited
• Subjects: Allosteric properties; Animals; Brain; Calcium Channels - genetics; Calcium Channels - metabolism; CELLBIO; Excitatory Amino Acid Agonists - metabolism; Glutamic Acid - metabolism; Ion Channel Gating; Kainic Acid - metabolism; Mice; MOLNEURO; Neurons - metabolism; Oocytes - cytology; Oocytes - physiology; Patch-Clamp Techniques; Protein Isoforms - genetics; Protein Isoforms - metabolism; Protein Structure, Tertiary; Protein Subunits - genetics; Protein Subunits - metabolism; Receptors, AMPA - genetics; Receptors, AMPA - metabolism; Rodents; Synaptic Transmission - physiology; SYSNEURO; Xenopus laevis; CELLBIO; SYSNEURO; MOLNEURO
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2008.11.009

Neuronal AMPA receptors autoinactivate at high concentrations of glutamate, i.e., the current declines at glutamate concentrations above 10–100 μM. The mechanisms underlying this phenomenon are unclear. Stargazin-like TARPs are AMPA receptor auxiliary subunits that modulate receptor trafficking and channel properties. Here, we found that neuronal AMPA receptors and recombinant AMPA receptors coexpressed with stargazin autoinactivate at high concentrations of glutamate, whereas recombinant AMPA receptors expressed alone do not. The reduction of currents at high glutamate concentrations is not associated with a reduction of AMPA receptor number, but rather with the loss of stargazin-associated allosteric modulation of channel gating. We show that receptor desensitization promotes the dissociation of TARP-AMPA receptor complexes in a few milliseconds. This dissociation mechanism contributes to synaptic short-term modulation. The results demonstrate a mechanism for dynamic regulation of AMPA receptor activity to tune synaptic strength.