Functional rescue of a defective angiotensin II AT1 receptor mutant by the Mas protooncogene

Earlier studies with Mas protooncogene, a member of the G-protein-coupled receptor family, have proposed this gene to code for a functional AngII receptor, however further results did not confirm this assumption. In this work we investigated the hypothesis that a heterodimeration AT(1)/Mas could res...

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Published in:	Regulatory peptides Vol. 141; no. 1-3; pp. 159 - 167
Main Authors:	SANTOS, Edson L, REIS, Rosana I, COSTA-NETO, Claudio M, PESQUERO, Joao B, SILVA, Ronaldo G, SHIMUTA, Suma I, PECHER, Christiane, BASCANDS, Jean-Loup, SCHANSTRA, Joost P, OLIVEIRA, Laerte, BADER, Michael, PAIV, Antonio C. M
Format:	Journal Article
Language:	English
Published:	Shannon Elsevier 07-06-2007 Amsterdam
Subjects:	Amino Acid Sequence Angiotensin II Angiotensin II - metabolism Animals Biological and medical sciences Cell Membrane Cell Membrane - metabolism Cercopithecus aethiops CHO Cells COS Cells Cricetinae Cricetulus Fluoresceins Fluorescent Antibody Technique, Direct Fluorescent Dyes Fundamental and applied biological sciences. Psychology Indoles Inhibitory Concentration 50 Inositol Phosphates Inositol Phosphates - analysis Inositol Phosphates - metabolism Models, Chemical Molecular Sequence Data Mutation Polymerase Chain Reaction Proto-Oncogenes Proto-Oncogenes - genetics Receptor, Angiotensin, Type 1 Receptor, Angiotensin, Type 1 - chemistry Receptor, Angiotensin, Type 1 - genetics Receptor, Angiotensin, Type 1 - metabolism Receptors, G-Protein-Coupled Receptors, G-Protein-Coupled - genetics Receptors, G-Protein-Coupled - metabolism Transfection Vertebrates: endocrinology Peptide hormone G-protein-coupled receptor AT1 angiotensin receptor AT1 receptor Octapeptide Renin angiotensin system Mas protooncogene Mutation Angiotensin II Dimerization Protooncogene G protein Biological receptor
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Summary:	Earlier studies with Mas protooncogene, a member of the G-protein-coupled receptor family, have proposed this gene to code for a functional AngII receptor, however further results did not confirm this assumption. In this work we investigated the hypothesis that a heterodimeration AT(1)/Mas could result in a functional interaction between both receptors. For this purpose, CHO or COS-7 cells were transfected with the wild-type AT(1) receptor, a non-functional AT(1) receptor double mutant (C18F-K20A) and Mas or with WT/Mas and C18F-K20A/Mas. Cells single-expressing Mas or C18F/K20A did not show any binding for AngII. The co-expression of the wild-type AT(1) receptor and Mas showed a binding profile similar to that observed for the wild-type AT(1) expressed alone. Surprisingly, the co-expression of the double mutant C18F/K20A and Mas evoked a total recovery of the binding affinity for AngII to a level similar to that obtained for the wild-type AT(1). Functional measurements using inositol phosphate and extracellular acidification rate assays also showed a clear recovery of activity for AngII on cells co-expressing the mutant C18F/K20A and Mas. In addition, immunofluorescence analysis localized the AT(1) receptor mainly at the plasma membrane and the mutant C18F-K20A exclusively inside the cells. However, the co-expression of C18F-K20A mutant with the Mas changed the distribution pattern of the mutant, with intense signals at the plasma membrane, comparable to those observed in cells expressing the wild-type AT(1) receptor. These results support the hypothesis that Mas is able to rescue binding and functionality of the defective C18F-K20A mutant by dimerization.
ISSN:	0167-0115 1873-1686
DOI:	10.1016/j.regpep.2006.12.030