4.8 Article

Homomeric GluA2(R) AMPA receptors can conduct when desensitized

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NATURE COMMUNICATIONS
卷 10, 期 -, 页码 -

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NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-12280-9

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资金

  1. MRC [MR/J002976/1, MR/J012998/1]
  2. Wellcome Trust [086185/Z/08/Z]
  3. BBSRC [BB/N015274/1]
  4. Wellcome Trust [086185/Z/08/Z] Funding Source: Wellcome Trust
  5. BBSRC [BB/N015274/1] Funding Source: UKRI
  6. MRC [MR/J012998/1, MR/J002976/1] Funding Source: UKRI

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Desensitization is a canonical property of ligand-gated ion channels, causing progressive current decline in the continued presence of agonist. AMPA-type glutamate receptors (AMPARs), which mediate fast excitatory signaling throughout the brain, exhibit profound desensitization. Recent cryo-EM studies of AMPAR assemblies show their ion channels to be closed in the desensitized state. Here we present evidence that homomeric Q/R-edited AMPARs still allow ions to flow when the receptors are desensitized. GluA2(R) expressed alone, or with auxiliary subunits (gamma-2, gamma-8 or GSG1L), generates large fractional steady-state currents and anomalous current-variance relationships. Our results from fluctuation analysis, single-channel recording, and kinetic modeling, suggest that the steady-state current is mediated predominantly by conducting desensitized receptors. When combined with crystallography this unique functional readout of a hitherto silent state enabled us to examine cross-linked cysteine mutants to probe the conformation of the desensitized ligand binding domain of functioning AMPAR complexes.

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