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The Journal of Neuroscience, October 25, 2006, 26(43):11220-11229; doi:10.1523/JNEUROSCI.2301-06.2006

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Cellular/Molecular
Isoform-Specific Early Trafficking of AMPA Receptor Flip and Flop Variants

Sarah K. Coleman,¹ Tommi Möykkynen,² Chunlin Cai,¹ Lotta von Ossowski,¹ Esa Kuismanen,¹ Esa R. Korpi,² and Kari Keinänen¹

¹Department of Biological and Environmental Sciences, Division of Biochemistry, Viikki Biocenter, and ²Institute of Biomedicine, Pharmacology, Biomedicum Helsinki, University of Helsinki, FIN-00014 Helsinki, Finland

Correspondence should be addressed to Kari Keinänen, Department of Biological and Environmental Sciences, Division of Biochemistry, FI-00014 University of Helsinki, Finland. Email: kari.keinanen{at}helsinki.fi

Flip and flop splice variants of AMPA receptor subunits are expressed in distinct but partly overlapping patterns and impart different desensitization kinetics to cognate receptor channels. In the absence of specific antibodies, isoform-specific differences in trafficking or localization of native flip and flop subunits remain uncharacterized. We report that in several transfected cell lines, transport of homomeric glutamate receptor (GluR)-D_flop receptors is largely blocked at the endoplasmic reticulum (ER) exit, whereas GluR-D_flip undergoes complex glycosylation and reaches the plasma membrane at >10x higher levels than GluR-D_flop, as determined by immunofluorescence, patch-clamp recordings and biochemical assays. The transport difference between flip and flop is independent of activity, is primarily determined by amino acid residue 780 (Leu in flop, Val in flip), and is manifested even in the secretion of the soluble ligand-binding domain, suggesting it is independent of oligomerization. Coexpression with stargazin or with the flip isoform rescues the surface expression of GluR-D_flop near to the level exhibited by GluR-D_flip. Our results demonstrate that the extracellular flip/flop region, via interactions with ER luminal splice form-specific protein(s), plays a hitherto unappreciated and important role in AMPA-receptor trafficking.

Key words: AMPA receptor; ER exit; flip/flop splice variants; GluR-D; GluR4; trafficking

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Received May 31, 2006; revised Sept. 18, 2006; accepted Sept. 18, 2006.

Correspondence should be addressed to Kari Keinänen, Department of Biological and Environmental Sciences, Division of Biochemistry, FI-00014 University of Helsinki, Finland. Email: kari.keinanen{at}helsinki.fi

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