Canals, M., Lopez-Gimenez, J. F. and Milligan, G. (2009) Cell surface delivery and structural re-organization by pharmacological chaperones of an oligomerization-defective α1b-adrenoceptor mutant demonstrates membrane targeting of GPCR oligomers. Biochemical Journal, 417(1), pp. 161-172. (doi: 10.1042/BJ20081227)
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Publisher's URL: http://dx.doi.org/10.1042/BJ20081227
Abstract
Many G protein-coupled receptors, including the α<sub>1b</sub>-adrenoceptor form homo-dimers or oligomers. Mutation of hydrophobic residues in transmembrane domains I and IV alters the organization of the α<sub>1b</sub>-adrenoceptor oligomer with transmembrane domain IV playing a critical role. These mutations also result in endoplasmic reticulum trapping of the receptor. Following stable expression of this α<sub>1b</sub>-adrenoceptor mutant cell surface delivery, receptor function and structural organization were recovered by treatment with a range of α<sub>1b</sub>-adrenoceptor antagonists that acted at the level of the endoplasmic reticulum. This was accompanied by maturation of the mutant receptor to a terminally N-glycosylated form and only this mature form was trafficked to the cell surface. Co-expression of the mutant receptor with an otherwise wild type form of the a1b-adrenoceptor that is unable to bind ligands resulted in this wild type variant also being retained in the endoplasmic reticulum. Ligand-induced cell surface delivery of the mutant α<sub>1b</sub>-adrenoceptor now allowed co-recovery to the plasma membrane of the ligand binding deficient mutant. These results demonstrate that interactions between α<sub>1b</sub>-adrenoceptor monomers occur at an early stage in protein synthesis, that ligands of the α<sub>1b</sub>-adrenoceptor can act as pharmacological chaperones to allow a structurally compromised form of the receptor to pass cellular quality control, that the mutated receptor is not inherently deficient in function and that an oligomeric assembly of ligand binding-competent and -incompetent forms of the a1b-adrenoceptor can be trafficked to the cell surface by binding of a ligand to only one component of the receptor oligomer.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Lopez-Gimenez, Dr Juan and Milligan, Professor Graeme and Canals Buj, Dr Meritxell |
| Authors: | Canals, M., Lopez-Gimenez, J. F., and Milligan, G. |
| Subjects: | Q Science > QH Natural history > QH345 Biochemistry |
| College/School: | College of Medical Veterinary and Life Sciences > School of Molecular Biosciences |
| Journal Name: | Biochemical Journal |
| Publisher: | Portland Press Ltd. |
| ISSN: | 0264-6021 |
| ISSN (Online): | 1470-8728 |
| Published Online: | 03 September 2008 |
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