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J. Biol. Chem., Vol. 282, Issue 28, 20676-20685, July 13, 2007

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Rescue of a Nephrogenic Diabetes Insipidus-causing Vasopressin V₂ Receptor Mutant by Cell-penetrating Peptides^*

Morad Oueslati, Ricardo Hermosilla, Eva Schönenberger, Viola Oorschot^¶, Michael Beyermann, Burkhard Wiesner, Antje Schmidt, Judith Klumperman^¶, Walter Rosenthal, and Ralf Schülein¹

From the Leibniz-Institut für Molekulare Pharmakologie, Robert-Rössle-Strae 10, 13125 Berlin, Germany, the Institut für Pharmakologie, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Thielallee 67-73, 14195 Berlin, Germany, and the ^¶Department of Cell Biology, University Medical Center and Institute for Biomembranes, 3584 CX Utrecht, The Netherlands

Mutant membrane proteins are frequently retained in the early secretory pathway by a quality control system, thereby causing disease. An example are mutants of the vasopressin V₂ receptor (V₂R) leading to nephrogenic diabetes insipidus. Transport-defective V₂Rs fall into two classes: those retained exclusively in the endoplasmic reticulum (ER) and those reaching post-ER compartments such as the ER/Golgi intermediate compartment. Although numerous chemical or pharmacological chaperones that rescue the transport of ER-retained membrane proteins are known, substances acting specifically in post-ER compartments have not been described as yet. Using the L62P (ER-retained) and Y205C (reaching post-ER compartments) mutants of the V₂R as a model, we show here that the cell-penetrating peptide penetratin and its synthetic analog KLAL rescue the transport of the Y205C mutant. In contrast, the location of the L62P mutant is not influenced by either peptide because the peptides are unable to enter the ER. We also show data indicating that the peptide-mediated transport rescue is associated with an increase in cytosolic Ca²⁺ concentrations. Thus, we describe a new class of substances influencing protein transport specifically in post-ER compartments.

Received for publication, December 18, 2006 , and in revised form, May 3, 2007.

^* This work was supported by Deutsche Forschungsgemeinschaft Grant SFB 449 and the European Commission-funded "ACTION" Project (Quality of Life, New Drugs and Treatment Strategies of Urinary Incontinence and Voiding Disorders Project QLK3-2001-00987). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 49-30-94793-255; Fax: 49-30-94793-109; E-mail: schuelein{at}fmp-berlin.de.

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