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J. Biol. Chem., Vol. 279, Issue 45, 47254-47263, November 5, 2004

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Pharmacochaperones Post-translationally Enhance Cell Surface Expression by Increasing Conformational Stability of Wild-type and Mutant Vasopressin V₂ Receptors^*

Stefan Wüller, Burkhard Wiesner, Anja Löffler¶, Jens Furkert, Gerd Krause, Ricardo Hermosilla¶, Michael Schaefer¶, Ralf Schülein, Walter Rosenthal¶, and Alexander Oksche¶||

From the Forschungsinstitut für Molekulare Pharmakologie, Campus Berlin Buch, Robert-Roessle-Str. 10, 13125 Berlin, Germany, the Kinderklinik der RWTH-Aachen, Pauwelsstr. 30, 52074 Aachen, Germany, and the ^¶Institut für Pharmakologie, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Thielallee 67-73, 14195 Berlin, Germany

Some membrane-permeable antagonists restore cell surface expression of misfolded receptors retained in the endoplasmic reticulum (ER) and are therefore termed pharmacochaperones. Whether pharmacochaperones increase protein stability, thereby preventing rapid degradation, or assist folding via direct receptor interactions or interfere with quality control components remains elusive. We now show that the cell surface expression and function (binding of the agonist) of the mainly ER-retained wild-type murine vasopressin V₂ receptor GFP fusion protein (mV₂R·GFP) is restored by the vasopressin receptor antagonists SR49059 and SR121463B with EC₅₀ values similar to their K_D values. This effect was preserved when protein synthesis was abolished. In addition, SR121463B rescued eight mutant human V₂Rs (hV₂Rs, three are responsible for nephrogenic diabetes insipidus) characterized by amino acid exchanges at the C-terminal end of transmembrane helix TM I and TM VII. In contrast, mutants with amino acid exchanges at the interface of TM II and IV were not rescued by either antagonist. The mechanisms involved in successful rescue of cell surface delivery are explained in a three-dimensional homology model of the antagonist-bound hV₂R.

Received for publication, July 19, 2004 , and in revised form, August 19, 2004.

^* The work was supported by the Deutsche Forschungsgemeinschaft (GK276/2) and the Fonds der Chemischen Industrie. 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.

The on-line version of this article (available at http://www.jbc.org) contains Supplementary Materials.

^|| To whom correspondence should be addressed: Thielallee 67-73, 14195 Berlin, Germany. Tel.: 49-30-8445-1860; Fax: 49-30-8445-1818; E-mail: alexander.oksche{at}medizin.fu-berlin.de.

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