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The Journal of Neuroscience, July 13, 2005, 25(28):6676-6686; doi:10.1523/JNEUROSCI.1079-05.2005

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Cellular/Molecular
Structural Determinants of 42 Nicotinic Acetylcholine Receptor Trafficking

Xiao-Qin Ren,¹ Shi-Bin Cheng,¹ Magdalen W. Treuil,² Jayanta Mukherjee,¹ Jayaraman Rao,² K. H. Braunewell,³ Jon M. Lindstrom,⁴ and Rene Anand^1,2

¹Neuroscience Center of Excellence and ²Department of Neurology, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, ³Signal Transduction Research Group, Neuroscience Research Center, Charité, University Medicine, 10117 Berlin, Germany, and ⁴Department of Neuroscience, University of Pennsylvania, Philadelphia, Pennsylvania 19104

The structural determinants of nicotinic acetylcholine receptor (AChR) trafficking have yet to be fully elucidated. Hydrophobic residues occur within short motifs important for endoplasmic reticulum (ER) export or endocytotic trafficking. Hence, we tested whether highly conserved hydrophobic residues, primarily leucines, in the cytoplasmic domain of the 42 AChR subunits were required for cell surface expression of 42 AChRs. Mutation of F350, L351, L357, and L358 to alanine in the 4 AChR subunit attenuates cell surface expression of mutant 42 AChRs. Mutation of F342, L343, L349, and L350 to alanine at homologous positions in the 2 AChR subunit abolishes cell surface expression of mutant 42 AChRs. The hydrophobic nature of the leucine residue is a primary determinant of its function because mutation of L343 to another hydrophobic amino acid, phenylalanine, in the 2 AChR subunit only poorly inhibits trafficking of mutant 42 AChR to the cell surface. All mutant 42 AChRs exhibit high-affinity binding for [³H]epibatidine. In both tsA201 cells and differentiated SH-SY5Y neural cells, wild-type 42 AChRs colocalize with the Golgi marker giantin, whereas mutant 42 AChRs fail to do so. The striking difference between mutant 4 versus mutant 2 AChR subunits on cell surface expression of mutant 42 AChRs points to a cooperative or regulatory role for the 4 AChR subunit and an obligatory role for the 2 AChR subunit in ER export. Collectively, our results identify, for the first time, residues within AChR subunits that are essential structural determinants of 42 AChR ER export.

Key words: cargo; export; endoplasmic reticulum; Golgi; nicotine; trafficking

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Received Oct 8, 2004; revised June 7, 2005; accepted June 8, 2005.

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