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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Signal Transduction Profiling of Angiotensin II Type 1 Receptor With Mutations Associated to Atrial Fibrillation in Humans

Full text
Author(s):
Simoes, Sarah C. [1] ; Balico-Silva, Andre L. [1] ; Parreiras-e-Silva, Lucas T. [1] ; Bitencourt, Andre L. B. [1] ; Bouvier, Michel [2, 3] ; Costa-Neto, Claudio M. [1]
Total Authors: 6
Affiliation:
[1] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Biochem & Immunol, Ribeirao Preto - Brazil
[2] Univ Montreal, Inst Res Immunol & Canc, Montreal, PQ - Canada
[3] Univ Montreal, Dept Biochem & Mol Med, Montreal, PQ - Canada
Total Affiliations: 3
Document type: Journal article
Source: FRONTIERS IN PHARMACOLOGY; v. 11, DEC 22 2020.
Web of Science Citations: 0
Abstract

The AT1 receptor (AT1R) has a major role in the Renin-Angiotensin System, being involved in several physiological events including blood pressure control and electrolyte balance. The AT1R is a member of the G protein coupled receptors (GPCR) family, classically known to couple G(alpha q) and engage beta-arrestin recruitment. Both G protein and arrestin signaling pathways are involved in modulation of different downstream kinases. A previous study reported that mutations in the AT1R (A244S and I103T-A244S) were positively correlated with higher risk of atrial fibrillation in men. Based on that report, we aimed to investigate if these mutations, including I103T only, could affect AT1R signal transduction profile, and consequently, implicate in atrial fibrillation outcome. To address that, we engineered an AT1R carrying the above-mentioned mutations, and functionally evaluated different signaling pathways. Phosphokinase profiler array to assess the mutations downstream effects on kinases and kinase substrates phosphorylation levels was used. Our results show that the I103T-A244S mutant receptor presents decreased beta-arrestin 2 recruitment, which could lead to a harmful condition of sustained G(alpha q) signaling. Moreover, the phosphokinase profiler array revealed that the same mutation led to downstream modulation of kinase pathways that are linked to physiological responses such as fibrous tissue formation, apoptosis and cell proliferation. (AU)

FAPESP's process: 16/08920-0 - Comparative analysis of the AT1 receptor signaling profile after activation by balanced and biased agonists by proteomic approach
Grantee:Sarah Capelupe Simões
Support Opportunities: Scholarships in Brazil - Doctorate
FAPESP's process: 12/20148-0 - Development of new ligands/drugs with selective agonism action (biased agonism) for receptors of the renin-angiotensin and kallikrein-kinin systems: new properties and new biotechnological applications
Grantee:Claudio Miguel da Costa Neto
Support Opportunities: Research Projects - Thematic Grants
FAPESP's process: 16/24120-3 - Study of non-canonical roles of G proteins as new signaling mechanisms with impact on discovery and development of new drugs
Grantee:Lucas Tabajara Parreiras e Silva
Support Opportunities: Research Grants - Young Investigators Grants
FAPESP's process: 15/50086-4 - Development of biosensors for monitoring signaling in subcellular compartments: a powerful molecular tool for drug discovery
Grantee:Claudio Miguel da Costa Neto
Support Opportunities: Regular Research Grants