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The Journal of Neuroscience, February 2, 2005, 25(5):1095-1102; doi:10.1523/JNEUROSCI.3568-04.2005

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Cellular/Molecular
Interaction with the Unfolded Protein Response Reveals a Role for Stargazin in Biosynthetic AMPA Receptor Transport

Wim Vandenberghe,¹ Roger A. Nicoll,^1,2 and David S. Bredt¹

Departments of ¹Physiology and ²Cellular and Molecular Pharmacology, University of California at San Francisco, San Francisco, California 94143

The transmembrane protein stargazin enhances levels of functional AMPA receptors at the neuronal plasma membrane and at synapses. To clarify the mechanism for this effect, we studied trafficking of the AMPA receptor subunit glutamate receptor 1 (GluR1) in transfected COS7 cells. GluR1 expressed poorly on the surface of these cells and was primarily retained in the endoplasmic reticulum (ER). Stargazin expression strongly increased the surface fraction of GluR1. This effect was not reduced by a dominant-negative dynamin mutant, suggesting that stargazin does not inhibit AMPA receptor endocytosis. Interestingly, upregulation of ER chaperones as part of the unfolded protein response (UPR) both mimicked and occluded the effect of stargazin, suggesting a role for stargazin in ER processing of AMPA receptors. Consistent with this idea, we detected UPR induction in cerebellar granule cells lacking stargazin. Finally, residual AMPA receptor currents in stargazin-deficient neurons were suppressed by inhibition of the UPR. These findings uncover a role for stargazin in AMPA receptor trafficking through the early compartments of the biosynthetic pathway. Furthermore, they provide evidence for modulation of AMPA receptor trafficking by the UPR.

Key words: glutamate; TARP; trafficking; endoplasmic reticulum; endocytosis; synaptic plasticity

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Received Aug 30, 2004; revised December 3, 2004; accepted December 13, 2004.

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