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RESEARCH ARTICLE |
1 DEPSN, UPR 2197, Institut de Neurobiologie Alfred Fessard, CNRS, Avenue de la Terrasse, F91198 Gif-sur-Yvette Cedex, France
2 UMR 144 CNRS Institut Curie, Laboratoire C Burg, 12 Rue Lhomond, 75005 Paris, France
3 Genaxis Biotechnology, Nîmes, France
* These authors contributed equally to this work
Author for correspondence (e-mail: vernier{at}iaf.cnrs-gif.fr)
Accepted June 26, 2001
The dopamine D2 receptor exists as a long (D2a) and a short (D2b) isoform generated by alternative splicing of the corresponding transcript, which modifies the length of the third cytoplasmic loop implicated in heterotrimeric G-protein-coupling. Anatomical data suggested that this segment regulates the intracellular traffic and localization of the receptor. To directly address this question we used a combination of tagging procedures and immunocytochemical techniques to detect each of the two D2 receptor isoforms. Surprisingly, most of the newly synthesized receptors accumulate in large intracellular compartments, the plasma membrane being only weakly labeled, without significant difference between the two receptor isoforms. Double labeling experiments showed that this localization corresponded neither to endosomal compartments nor to the Golgi apparatus. The D2 receptor is mostly retained in the endoplasmic reticulum (ER), the long isoform more efficiently than the short one. It is accompanied by a striking vacuolization of the ER, roughly proportional to the expression levels of the two receptor isoforms. This phenomenon is partly overcome by treatment with pertussis toxin. In addition, an intrinsic activity of the D2 receptor isoforms is revealed by [35S]-GTP
S binding and cAMP assay, which suggested that expression of weakly but constitutively active D2 receptors promotes activation of heterotrimeric G protein inside the secretory pathway. This mechanism may participate in the regulation of the cellular traffic of the D2 receptors isoforms.
Key words: Heterotrimeric G proteins, Cell compartments, Intrinsic activity
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