Cell surface delivery and structural re-organization by pharmacological chaperones of an oligomerization-defective α1b-adrenoceptor mutant demonstrates membrane targeting of GPCR oligomers

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 α1b-adrenoceptor form homo-dimers or oligomers. Mutation of hydrophobic residues in transmembrane domains I and IV alters the organization of the α1b-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 α1b-adrenoceptor mutant cell surface delivery, receptor function and structural organization were recovered by treatment with a range of α1b-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 α1b-adrenoceptor now allowed co-recovery to the plasma membrane of the ligand binding deficient mutant. These results demonstrate that interactions between α1b-adrenoceptor monomers occur at an early stage in protein synthesis, that ligands of the α1b-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 > Institute of Molecular Cell and Systems Biology
Journal Name:Biochemical Journal
Publisher:Portland Press Ltd.
ISSN:0264-6021
ISSN (Online):1470-8728
Published Online:03 September 2008
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
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389781The quaternary structure of G-protein coupled receptors - implications for function drug design. Programme grant support renewalGraeme MilliganMedical Research Council (MRC)G9811527Institute of Neuroscience and Psychology