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

Autor(es)

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]

Afiliação do(s) autor(es)

^[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

• Tipo de documento: Artigo Científico
• Fonte: FRONTIERS IN PHARMACOLOGY; v. 11, DEC 22 2020.
• Citações Web of Science: 0

Resumo

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)

• Processo FAPESP: 16/08920-0 - Análise comparativa do perfil de sinalização do receptor AT1 após a ativação por agonistas balanceados e tendenciosos ("biased agonists") por abordagem proteômica.
• Beneficiário: Sarah Capelupe Simões
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 12/20148-0 - Desenvolvimento de novos ligantes/drogas com ação agonística seletiva ("biased agonism") para receptores dos sistemas renina-angiotensina e calicreínas-cininas: novas propriedades e novas aplicações biotecnológicas
• Beneficiário: Claudio Miguel da Costa Neto
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 16/24120-3 - Estudo dos papéis não-canônicos de proteínas G como novos mecanismos de sinalização celular com impacto na descoberta e desenvolvimento de fármacos
• Beneficiário: Lucas Tabajara Parreiras e Silva
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores
• Processo FAPESP: 15/50086-4 - Development of biosensors for monitoring signaling in subcellular compartments: a powerful molecular tool for drug discovery
• Beneficiário: Claudio Miguel da Costa Neto
• Modalidade de apoio: Auxílio à Pesquisa - Regular