title: Rescue of a nephrogenic diabetes insipidus-causing vasopressin V2 receptor mutant by cell-penetrating peptides.
abstract: 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 V(2) receptor (V(2)R) leading to nephrogenic diabetes insipidus. Transport-defective V(2)Rs 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 V(2)R 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 Ca(2+) concentrations. Thus, we describe a new class of substances influencing protein transport specifically in post-ER compartments.
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
authors.forename: Morad
authors.initials: M
authors.lastname: Oueslati
authors.forename: Ricardo
authors.initials: R
authors.lastname: Hermosilla
authors.forename: Eva
authors.initials: E
authors.lastname: Schönenberger
authors.forename: Viola
authors.initials: V
authors.lastname: Oorschot
authors.forename: Michael
authors.initials: M
authors.lastname: Beyermann
authors.forename: Burkhard
authors.initials: B
authors.lastname: Wiesner
authors.forename: Antje
authors.initials: A
authors.lastname: Schmidt
authors.forename: Judith
authors.initials: J
authors.lastname: Klumperman
authors.forename: Walter
authors.initials: W
authors.lastname: Rosenthal
authors.forename: Ralf
authors.initials: R
authors.lastname: Schülein
mesh_terms: D019943:Amino Acid Substitution; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects* / Q000235:genetics; D002352:Carrier Proteins / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D057846:Cell-Penetrating Peptides; D018500:Diabetes Insipidus, Nephrogenic / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D006056:Golgi Apparatus / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D018832:Molecular Chaperones / Q000378:metabolism; D020125:Mutation, Missense; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D017483:Receptors, Vasopressin / Q000235:genetics / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D057846:Cell-Penetrating Peptides; D018832:Molecular Chaperones; D017483:Receptors, Vasopressin; C414409:penetratin; D002118:Calcium