Type 3 muscarinic receptor activation and association with ADP-rybosilation factor 1 and 6 on the pancreatic beta-cell function: downstream signalling pathways, islet arquitecture and insulin secretion

• Grant number: 12/14993-9
• Support Opportunities: Research Grants - Young Investigators Grants
• Duration: July 01, 2013 - June 30, 2016
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Helena Cristina de Lima Barbosa
• Grantee: Helena Cristina de Lima Barbosa
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated researchers: Antonio Carlos Boschiero ; Sandra Mara Ferreira
• Associated scholarship(s): 15/15059-6 - Role of ARHGAP21 in cell differentiation and growth processes during the development of endocrine pancreas in C57BL/6 mice, BP.IC; 14/03547-3 - In vivo effect of reduced expression of ARHGAP21 on glucose homeostasis and expression of key proteins of glucose metabolism in pancreatic islet and peripheral tissues, BP.IC; 13/12827-7 - Type 3 muscarinic receptor activation and association with ADP-rybosilation factor 1 and 6 on the pancreatic beta-cell function: downstream signalling pathways, islet arquitecture and insulin secretion, BP.JP

Abstract

Type 2 diabetes mellitus (T2D) is a heterogenic disorder characterised by chronic hyperglycemia, due to the combination of insulin resistance in peripheral tissues and a deficient insulin secretion in pancreatic islets. The cholinergic stimulation is one of the most important mechanisms that regulate the beta-cell function, in which M3 muscaric receptor activation results in an increase in the citoplasmic calcium concentration and an increment in nutrient-induced insulin secretion. There are evidences that M3 receptor interacts with small GTPases named ARFs in astrocitome, renal cells and neutrophills. Moreover, it is known that ARFs are involved in signalling pathways that regulates adherent junction turnover, through the distribution and traffic of the adhesion molecules complex components in epithelial cells, regulating cellular morphological changes. In addition, ARFs interact with ARHGAP21, a GTPase-activating protein that negatively controls insulin secretion in beta-cells. Then, for better understanding the beta-cell failure during the T2D progression, it is necessary to elucidate the M3 receptor downstream components, pancreatic beta-cell structure, communication and function, especially the glucose-induce insulin secretion. In addition, this knowledge will help to find new strategies to avoid and/or treat T2D. In this way, using MIN6 beta-cells and C57BL/6 mouse pancreatic islets, this project is aimed at elucidate: a) the molecular mechanisms involved in the ADP-rybosilation factor 1 and 6; b) its interaction with the GAP ARHGAP21 in the stimulation of the cholinergic muscarinic receptor M3 and; c) the regulation of cellular adhesion molecules ECAD on the pancreatic beta-cells functions. (AU)

Scientific publications

(5)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

SOARES, GABRIELA M.; ZANGEROLAMO, LUCAS; AZEVEDO, ELIS G.; COSTA-JUNIOR, JOSE M.; CARNEIRO, EVERARDO M.; SAAD, SARA T.; BOSCHERO, ANTONIO C.; BARBOSA-SAMPAIO, HELENA C.. Whole body ARHGAP21 reduction improves glucose homeostasis in high-fat diet obese mice. Journal of Cellular Physiology, v. 233, n. 9, p. 7112-7119, SEP 2018. (15/12611-0, 12/14993-9)

ROSA, LUCAS R. O.; SOARES, GABRIELA M.; SILVEIRA, LEONARDO R.; BOSCHERO, ANTONIO C.; BARBOSA-SAMPAIO, HELENA C. L.. ARHGAP21 as a master regulator of multiple cellular processes. Journal of Cellular Physiology, v. 233, n. 11, p. 8477-8481, NOV 2018. (12/14993-9, 13/07607-8, 15/12611-0)

SOARES, GABRIELA MOREIRA; ZANGEROLAMO, LUCAS; COSTA-JUNIOR, JOSE MARIA; VETTORAZZI, JEAN FRANCIESCO; CARNEIRO, EVERARDO MAGALHAES; SAAD, SARA TERESINHA; BOSCHERO, ANTONIO CARLOS; BARBOSA-SAMPAIO, HELENA CRISTINA. Whole-Body ARHGAP21-Deficiency Improves Energetic Homeostasis in Lean and Obese Mice. FRONTIERS IN ENDOCRINOLOGY, v. 10, MAY 29 2019. (12/14993-9, 15/12611-0)

ROSA, LUCAS RODOLFO DE OLIVEIRA; VETTORAZZI, JEAN FRANCIESCO; ZANGEROLAMO, LUCAS; CARNEIRO, EVERARDO MAGALHAES; BARBOSA, HELENA CRISTINA DE LIMA. UDCA receptors and their role on pancreatic beta cell. PROGRESS IN BIOPHYSICS & MOLECULAR BIOLOGY, v. 167, p. 26-31, DEC 2021. (19/23951-7, 12/14993-9, 15/12611-0, 13/07607-8, 18/06363-1)

ZANGEROLAMO, LUCAS; SOARES, GABRIELA MOREIRA; VETTORAZZI, JEAN FRANCIESCO; DO AMARAL, MARIA ESMERIA; CARNEIRO, EVERARDO MAGALHAES; OLALLA-SAAD, SARA TERESINHA; BOSCHERO, ANTONIO CARLOS; BARBOSA-SAMPAIO, HELENA CRISTINA. ARHGAP21 deficiency impairs hepatic lipid metabolism and improves insulin signaling in lean and obese mice. Canadian Journal of Physiology and Pharmacology, v. 97, n. 11, p. 1018-1027, NOV 2019. (12/14993-9, 15/23729-1, 15/12611-0)