Autoinactivation of neuronal AMPA receptors via glutamate-regulated TARP interaction.
Neuronal AMPA receptors autoinactivate at high concentrations of glutamate, i.e., the current declines at glutamate concentrations above 10-100 microM. 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.
Morimoto-Tomita
Megumi
M
Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Zhang
Wei
W
Straub
Christoph
C
Cho
Chang-Hoon
CH
Kim
Kwang S
KS
Howe
James R
JR
Tomita
Susumu
S
D000818:Animals; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D018690:Excitatory Amino Acid Agonists / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D015640:Ion Channel Gating; D007608:Kainic Acid / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D009865:Oocytes / Q000166:cytology / Q000502:physiology; D018408:Patch-Clamp Techniques; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism*; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology; D014982:Xenopus laevis
C113940:Cacng2 protein, mouse; D015220:Calcium Channels; D018690:Excitatory Amino Acid Agonists; D020033:Protein Isoforms; D021122:Protein Subunits; D018091:Receptors, AMPA; D018698:Glutamic Acid; D007608:Kainic Acid