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Pharmacochaperones post-translationally enhance cell surface expression by increasing conformational stability of wild-type and mutant vasopressin V2 receptors
 
Diabetes OD > Development and Function of Pancreas and Immunity > Journal Article

(Journal Article): Pharmacochaperones post-translationally enhance cell surface expression by increasing conformational stability of wild-type and mutant vasopressin V2 receptors
 
Wuller S, Wiesner B, Loffler A, Furkert J, Krause G, Hermosilla R, Schaefer M, Schulein R, Rosenthal W, Oksche A (Charite, Institut fur Pharmakologie, Berlin 14195, Germany, alexander.oksche@medizin.fu-berlin.de )
 
IN: J Biol Chem 2004; 279(45):47254-47263
Impact Factor(s) of J Biol Chem: 6.355 (2004), 6.482 (2003), 7.258 (2001)

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ABSTRACT: 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 KD 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 TMI and TMVII. 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 3D homology model of the antagonist-bound hV2R.

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