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A proteomic analysis has revealed a previously unknown additional subunit of the AMPA-type glutamate receptor (AMPAR). This ligand-gated ion channel handles much of the excitatory neurotransmission and synaptic plasticity in the brain, and its trafficking and function is altered by amyloid-β. In a study published in today’s Science, Bernd Fakler and Nikolaj Klöcker at the University of Freiburg in Germany report that most of the AMPARs in rat and mouse brain contain small transmembrane proteins of the cornichon family. Besides being yummy pickles, cornichons are a family of AMPAR accessory proteins. They are the second family to be discovered, after the transmembrane AMPAR regulatory proteins (TARPs), but the cornichons are associated with a larger proportion of AMPARs (at 70 percent) than the TARPs are (30 percent). Like TARPs, the cornichon proteins work to increase surface expression of AMPARs, and they alter channel function.

The two cornichon homologs CNIH-2 and CNIH-3 turned up when lead authors Jochen Schwenk, Nadine Harmel, and Gerd Zolles purified glutamate receptors from rat brain using antibodies to the pore-forming GluR subunits, and subjected the complexes to mass spectrometry analysis. The cornichon proteins were previously identified in fruit flies, where they play a role in the trafficking of transmembrane proteins out of the endoplasmic reticulum.

The cornichon proteins are structurally unrelated to TARPs. In an accompanying commentary, Cezar Tigaret and Daniel Choquet of the University of Bordeaux in France suggest that having a variety of accessory proteins may enable exquisitely fine tuning of AMPAR distribution and function.

In Alzheimer disease, Aβ causes synaptic failure, and some studies have associated this with the removal of AMPA receptors from synapses (see ARF related news story; Almeida et al., 2005; ARF related news story; and Hsieh et al., 2006). It remains to be seen how that happens, but the TARPs and now cornichon proteins may well be one place to look.—Pat McCaffrey.

References:
Schwenk J, Harmel N, Zolles G, Bildl W, Kulik A, Heimrich B, Chisaka O, Jonas P, Schulte U, Fakler G, Klocker N. Functional Proteomics Identify Cornichon Proteins as Auxiliary Subunits of AMPA Receptors. Science. 5 March 2009: 323;1313-1319. Abstract

Tigaret C, Choquet D. More AMPAR garnish. Science. 5 March 2009: 323;1295-1296. Abstract

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  1. This is a terrific paper that will change the way we think about AMPA receptors at a synapse. This is likely to have relevance for AD, although I am not sure it has been established yet that Aβ has a direct effect on AMPA receptors.

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References

News Citations

  1. Amyloid-β Zaps Synapses by Downregulating Glutamate Receptors
  2. AMPA Receptors: Going, Going, Gone in Aβ-exposed Synapses, PSD95 Knockouts

Paper Citations

  1. . Beta-amyloid accumulation in APP mutant neurons reduces PSD-95 and GluR1 in synapses. Neurobiol Dis. 2005 Nov;20(2):187-98. PubMed.
  2. . AMPAR removal underlies Abeta-induced synaptic depression and dendritic spine loss. Neuron. 2006 Dec 7;52(5):831-43. PubMed.
  3. . Functional proteomics identify cornichon proteins as auxiliary subunits of AMPA receptors. Science. 2009 Mar 6;323(5919):1313-9. PubMed.
  4. . Neuroscience. More AMPAR garnish. Science. 2009 Mar 6;323(5919):1295-6. PubMed.

Further Reading

Papers

  1. . Functional proteomics identify cornichon proteins as auxiliary subunits of AMPA receptors. Science. 2009 Mar 6;323(5919):1313-9. PubMed.
  2. . Neuroscience. More AMPAR garnish. Science. 2009 Mar 6;323(5919):1295-6. PubMed.

News

  1. Amyloid-β Zaps Synapses by Downregulating Glutamate Receptors
  2. AMPA Receptors: Going, Going, Gone in Aβ-exposed Synapses, PSD95 Knockouts

Primary Papers

  1. . Functional proteomics identify cornichon proteins as auxiliary subunits of AMPA receptors. Science. 2009 Mar 6;323(5919):1313-9. PubMed.
  2. . Neuroscience. More AMPAR garnish. Science. 2009 Mar 6;323(5919):1295-6. PubMed.