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G-protein coupled receptor Folding and Misfolding

110-187 disulfide bond

110-187 disulfide bond is missing in cannabinoid receptors, ref. Onaivi, E.S., C.M. Leonard, H. Ishiguro, P.W. Zhang, Z. Lin, B.E. Akinshola, and G.R. Uhl, Endocannabinoids and cannabinoid receptor genetics. Prog Neurobiol, 2002. 66(5): p. 307-44 (otherwise this review is mostly on genetics)

Rescue of misfolded receptors

concept of "pharmacological chaperones": Morello, J.P., U.E. Petaja-Repo, D.G. Bichet, and M. Bouvier, Pharmacological chaperones: a new twist on receptor folding. Trends Pharmacol Sci, 2000. 21(12): p. 466-9:

    - ligands with pharmacological selectivity can rescue targeting and function of misfolded proteins

    - examples for such ligands:    

        cystic fibrosis                            cystic fibrosis TM conductance regulator (CFTR)        glycerol, dimethylsulfoxide (DMSO), trimethylamine-N-oxide (TMAO)

        emphysema and liver disease    alpha1-antitrypsin                                                          glycerol

        nephrogenic diabetes insipidus  aquaporin-2                                                                   glycerol, DMSO, TMAO

        nephrogenic diabetes insipidus  Vasopressin V2 receptor                                               SR121463A, VPA985

        Retinitis pigmentosa                   rhodopsin                                                                      11-cis retinal

        Fabry                                          alpha-galactosidase A                                                   1-deoxy-galactonojirimycin

        Cancer                                        p53                                                                                CP31398, CP257042

        none                                            P-glycoprotein                                                               capsaicin, cyclosporin, vinblastin, verapamil

    - best example for misfolding disease is cystic fibrosis: Delta F508 mutation in CFTR is a trafficking mutation that blocks maturation of the protein in the ER and targets it for premature proteolysis. If the mutant protein is redirected to the cell surface, a healthy cell is restored.

    - low temperature or chemical agents such as glycerol, DMSO, TMAO  slow down the misfolding and/or degradation processes, so that correctly folded CFTR can escape to the cell surface

    - for V2 receptor and for rhodopsin, ligand can increase the proportion of folded protein (rhodopsin is not mentioned in the Morello et al paper, but is also a good example)