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cAMP responsive element (CRE) participation in the SLC2A4 regulation by sympathetic nervous system

Grant number: 13/26616-8
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): May 01, 2014
Effective date (End): October 31, 2016
Field of knowledge:Biological Sciences - Physiology - Physiology of Organs and Systems
Cooperation agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
Principal Investigator:Ubiratan Fabres Machado
Grantee:Ana Bárbara Teixeira Alves Wagner
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:12/04831-1 - New players in glycemic control and chronic complications of Diabetes mellitus: preventive and therapeutic perspectives, AP.TEM

Abstract

Slc2a4 (Solute carrier 2a4) is the gene that encodes for GLUT4 protein, the insulin-sensitive glucose transporter, expressed in muscle cells and adipocytes. Altered GLUT4 expression is directly correlated with alterations in glycemic homeostasis. Slc2a4 gene promoter has specific binding-sites in which transcriptional factors can bind to induce or repress the gene expression. The effect of sympathetic nervous system on glucose metabolism is mediated by both circulating epinephrine and the direct sympathetic innervations in the skeletal muscle. When epinephrine binds to stimulatory G protein-coupled receptors, it activates adenylyl cyclases, which catalyse the production of cAMP from ATP. cAMP activates PKA which activates CREB (cAMP Responsive Element-Binding protein). CREB homodimerizes and binds to a conserved CRE (cAMP Responsive Element) region on DNA, promoting transcription. Skeletal muscle is the major site involved in the insulin-dependent glucose uptake mediated by GLUT4. It has been demonstrated in skeletal muscle, that the ²-adrenergic system modulates the expression of Slc2a4/GLUT4 during fasting and that the high sympathetic activity, found in hypertensive animals, increases the Slc2a4 expression in experimental diabetes. However how this regulation occurs is far from being clearly understood. This project is aimed at testing the hypothesis that the Slc2a4 gene has the CRE region, and that this can be the main pathway by which the sympathetic activity stimulates the Slc2a4 expression in muscle. For this, we will make specific studies of electrophoretic mobility assay (to test potential targeting domains as responsive to cAMP) and cell transfection (to confirm the stimulatory effect on the transcription). Additionally, we will test the transcriptional activity of this element in experimental conditions of high or low sympathetic activity. Therefore the aim of this study is to elucidate the transcriptional mechanisms by which the sympathetic autonomic nervous system stimulates the Slc2a4 in skeletal muscle. (AU)

Scientific publications
(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)
YONAMINE, CAIO Y.; ALVES-WAGNER, ANA B.; ESTEVES, V, JOAO; OKAMOTO, MARISTELA M.; CORREA-GIANNELLA, MARIA L.; GIANNELLA-NETO, DANIEL; MACHADO, UBIRATAN F. Diabetes induces tri-methylation at lysine 9 of histone 3 at Slc2a4 gene in skeletal muscle: A new target to improve glycemic control. Molecular and Cellular Endocrinology, v. 481, p. 26-34, FEB 5 2019. Web of Science Citations: 0.

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