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Autoinactivation of neuronal AMPA receptors via glutamate-regulated TARP interaction.

ABSTRACT: 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.

SUBMITTER: Morimoto-Tomita M

PROVIDER: S-EPMC2649795 | biostudies-literature | 2009 Jan

REPOSITORIES: biostudies-literature

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Autoinactivation of neuronal AMPA receptors via glutamate-regulated TARP interaction.

Morimoto-Tomita Megumi M Zhang Wei W Straub Christoph C Cho Chang-Hoon CH Kim Kwang S KS Howe James R JR Tomita Susumu S

Neuron 20090101 1

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 AM ...[more]

PMID: 19146816

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Project description:BackgroundExcitation/inhibition imbalance (E/I imbalance), which involves an increase of alpha-amino-3-hydroxy-5-methyl-4-isoxazole (AMPA) receptors (AMPARs) and decrease of gamma-aminobutyric acid type A (GABA) type A receptors (GABAaRs) on the neuron surface, has been documented in the pathogenesis of seizures. Notably, it has been established that both the glutamate receptor subunit 2 (GluR2) of AMPARs and beta 2/3 subunits of GABAaRs (Gabrb2+3) participate in the recycling mechanism mediated by the kinesin heavy chain isoform 5A (KIF5A), which determines the number of neuron surface receptors. However, it remains unclear whether receptor recycling is involved in the pathogenesis of seizures.MethodsTwelve adult male Sprague-Dawley rats were randomly allocated to the normal control (Ctl) group (n=6) and the pentylenetetrazol (PTZ)-induced seizure (Sez) group (n=6). The rats in the Ctl group were treated with saline. The rats in the Sez group received an intraperitoneal injection of PTZ at an initial dose of 40 mg/kg. Primary cultured neurons were obtained from newborn rats (24-hour-old). The neurons were exposed to magnesium-free (Mg2+-free) extracellular fluid for 3 hours to establish the seizure model in vitro. We detected the electrophysiology of the seizure model, the expression levels of KIF5A, GluR2, and Gabrb2+3, the recycling ratio of GluR2 and Gabrb2+3, the interaction between KIF5A and GluR2, and the interaction between KIF5A and Gabrb2+3.ResultsIn the Sez group, the expression of GluR2 on the cell surface was increased and the expression of Gabrb2+3 on the cell surface was decreased. The amplitude and frequency of action potentials were significantly increased in the Mg2+-free group. The amplitude and decay time of AMPAR-mediated miniature excitatory postsynaptic currents were increased in the Mg2+-free group. The amplitude and decay time of miniature inhibitory postsynaptic currents were decreased in the Mg2+-free group. The recycling ratio of GluR2 was increased and the recycling ratio of Gabrb2+3 was decreased in the Mg2+-free group. The interaction between KIF5A and GluR2 was increased, and the interaction between KIF5A and Gabrb2+3 was decreased in the seizure model in vivo and in vitro.ConclusionsThe recycling of AMPA receptors/GABAa receptors is related to E/I imbalance and may be regulated by KIF5A.

Dataset Information

Autoinactivation of neuronal AMPA receptors via glutamate-regulated TARP interaction.

Publications

Autoinactivation of neuronal AMPA receptors via glutamate-regulated TARP interaction.

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