Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.31 (AMP-activated protein kinase)
 13,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glucose transport into muscle is important for the maintenance of normoglycemia. Thus, understanding mechanisms that regulate expression of GLUT4, the main glucose transporter in skeletal muscle, is important to identify targets for the treatment of diabetes. Exercise increases the expression of GLUT4 mRNA and protein, and we have been investigating the mechanisms involved. Transcription of the GLUT4 gene is transiently activated after an acute bout of exercise and GLUT4 protein can be increased as much as two- to threefold after a few days of repeated exercise bouts. Studies of the GLUT4 promoter have identified two sets of DNA sequences that are important for metabolic regulation and also for increased transcription of the gene in response to exercise. These DNA elements have been shown to bind the transcription factors myocyte enhancer factor 2 (MEF2) and GLUT4 enhancer factor (GEF). The mechanisms that activate these proteins remain one of the important areas of research in this field. Signals that link muscle contraction to the activation of transcription factors (MEF2, GEF) involved in increased expression of GLUT4 during exercise is another area needing further research. Two signals that show promise are changes in the energy charge (acting through AMP activated kinase [AMPK]) and changes in intracellular calcium (acting through calcineurin [a calcium-calmodulin activated phosphatase] and calcium-calmodulin activated kinase [CAMK]). There is good evidence that both increased AMPK activity and increased CAMK activity cause increased transcription of the GLUT4 gene. It remains to be demonstrated that exercise is acting through one or both of these mechanisms.
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PMID:Regulation of GLUT4 gene expression during exercise. 1523 26

As the primary glucose transporter in skeletal muscle, GLUT4 is an important factor in the regulation of blood glucose. We previously reported that stimulation of AMP-activated protein kinase (AMPK) with 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside (AICAR) increased GLUT4 expression in muscle. GLUT4 enhancer factor (GEF) and myocyte enhancer factor 2 (MEF2) have been shown to be important for normal GLUT4 expression because deletion or truncation of the consensus sequences on the promoter causes depressed GLUT4 mRNA expression. This led to the current study to investigate possible roles for GEF and MEF2 in mediating the activation of GLUT4 gene transcription in response to AMPK. Here we show that, although AMPK does not appear to phosphorylate MEF2A, AMPK directly phosphorylates the GEF protein in vitro. MEF2 and GEF are activated in response to AMPK as we observed translocation of both to the nucleus after AICAR treatment. Nuclear MEF2 protein content was increased after 2 h, and GEF protein was increased in the nucleus 1 and 2 h post-AICAR treatment. Last, GEF and MEF2 increase in binding to the GLUT4 promoter within 2 h after AICAR treatment. Thus we conclude that GEF and MEF2 mediate the AMPK-induced increase in transcription of skeletal muscle GLUT4. AMPK can phosphorylate GEF and in response to AICAR, GEF, and MEF2 translocate to the nucleus and have increased binding to the GLUT4 promoter.
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PMID:Regulation of muscle GLUT4 enhancer factor and myocyte enhancer factor 2 by AMP-activated protein kinase. 1610 57