University of Dundee

About: University of Dundee is a education organization based out in Dundee, United Kingdom. It is known for research contribution in the topics: Population & Protein kinase A. The organization has 19258 authors who have published 39640 publications receiving 1919433 citations. The organization is also known as: Universitas Dundensis & Dundee University.

Glycogen Synthase Kinase-3 from Rabbit Skeletal Muscle

Abstract: Publisher Summary This chapter discusses glycogen synthase kinase-3 from rabbit skeletal muscle. Glycogen synthase kinase-3 is one of the five glycogen synthase kinases that are identified in skeletal muscle, and is of major importance in determining the kinetic properties of glycogen synthase in vivo. It catalyzes the phosphorylation of three serine residues on glycogen synthase, converting the enzyme from a form that is almost fully active in the absence of glucose-6P, to one that is largely dependent on this allosteric activator. Glycogen synthase kinase-3 also has a second activity that is not shared by any other protein kinase—namely, the ability to activate an enzyme termed the MgATP-dependent protein phosphatase. Glycogen synthase may also contain traces of a modified form of phosphorylase kinase that has lost its sensitivity to regulation by calcium ions, and is therefore, no longer inhibited by ethylene glycol tetraacetic acid (EGTA). This is largely removed by passing glycogen synthase through phosphocellulose.

5‐Aminoimidazole‐4‐Carboxamide Ribonucleoside

Abstract: The AMP-activated protein kinase (AMPK) is believed to protect cells against environmental stress (e.g. heat shock) by switching off biosynthetic pathways, the key signal being elevation of AMP. Identification of novel targets for the kinase cascade would be facilitated by development of a specific agent for activating the kinase in intact cells. Incubation of rat hepatocytes with 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) results in accumulation of the monophosphorylated derivative (5-aminoimidaz-ole-4-carboxamide ribonucleoside; ZMP) within the cell. ZMP mimics both activating effects of AMP on AMPK, i.e. direct allosteric activation and promotion of phosphorylation by AMPK kinase. Unlike existing methods for activating AMPK in intact cells (e.g. fructose, heat shock), AICAR does not perturb the cellular contents of ATP, ADP or AMP. Incubation of hepatocytes with AICAR activates AMPK due to increased phosphorylation, causes phosphorylation and inactivation of a known target for AMPK (3-hydroxy-3-methylglutaryl-CoA reductase), and almost total cessation of two of the known target pathways, i.e. fatty acid and sterol synthesis. Incubation of isolated adipocytes with AICAR antagonizes isoprenaline-induced lipolysis. This provides direct evidence that the inhibition by AMPK of activation of hormone-sensitive lipase by cyclic-AMP-dependent protein kinase, previously demonstrated in cell-free assays, also operates in intact cells. AICAR should be a useful tool for identifying new target pathways and processes regulated by the protein kinase cascade.

The genetic architecture of type 2 diabetes

Abstract: The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.