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First published online 26 September 2006
doi: 10.1242/jcs.03189

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Role of the C-terminal di-leucine motif of 5-HT_1A and 5-HT_1B serotonin receptors in plasma membrane targeting

INSERM, U677, University Pierre et Marie Curie, Paris 75013, France

^* Author for correspondence (e-mail: darmon{at}ext.jussieu.fr)

Accepted 25 July 2006

The 5-HT_1A and 5-HT_1B serotonin receptors exhibit different subcellular localizations in neurons. Evidence has been reported that the C-terminal domain is involved in the somato-dendritic and axonal targeting of 5-HT_1AR and 5-HT_1BR, respectively. Here we analyzed the consequences of the mutation of a di-leucine motif and palmitoylated cysteines within this domain. Replacement of I414-I415 by a di-alanine in 5-HT_1AR led to endoplasmic reticulum (ER) sequestration of the corresponding mutant expressed in cell lines as well as in hippocampal neurons in culture. Furthermore, di-leucine-mutated receptors were unable to bind 5-HT_1A agonists and presented a major deficit in their glycosylation state, suggesting that they are misfolded. By contrast, mutation of the di-leucine motif in the C-terminal domain of 5-HT_1BR had no major consequence on its subcellular targeting. However, in the case of the 1ActB chimera (substitution of the C-terminal domain of the 5-HT_1BR into 5-HT_1AR), this mutation was also found to cause sequestration within the ER. Replacement of palmitoylated cysteines by serines had no consequence on either receptor type. These data indicate that the di-leucine motif of the 5-HT_1AR and 5-HT_1BR tails is implicated in proper folding of these receptors, which is necessary for their ER export.

Key words: Di-leucine motif, Palmitoylation, Endoplasmic reticulum, Folding, 5-HT_1A, 5-HT_1B

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