The fundamental goal of this research program is to advance understanding of the molecular mechanisms by which extracellular agents, such as hormones, regulate intracellular processes. The specific system under study is the control of glycogen metabolism by hormones such as insulin, glucagon, epinephrine (acting via alpha- or beta-adrenergic receptors) and vasopressin. The work emphasizes the role of the multiple phosphorylation of glycogen synthase in regulation of this enzyme and the functional rationale for the existence of tissue specific isozymes of glycogen synthase in liver and muscle, the two main reserves of mammalian glycogen. The immediate aims are as follows: (i) The extension of primary structural analysis, mostly of the liver isozyme, with identification of the sites phosphorylated by different protein kinases. (ii) The cloning of cDNA's encoding liver and muscle isozymes. These two aims will permit important comparisons of the amino acid sequences of the two isozymes. (iii) Enzymological definition of a class of enzymes (F-A/GSK-3) that recognize an important proline/serine rich regulatory segment of both isozymes together with mechanistic studies of that recognition process using synthetic peptide models of this pro/ser rich region. (iv) Structure/function studies aimed at improved understanding of the interactions among the catalytic site, the allosteric (glucose-6-P) site, and the phosphorylation sites of glycogen synthase. It is hoped ultimately to bring to bear the technique of site directed mutagenesis to this problem. (v) Analysis of the phosphorylation of glycogen synthase in whole cell models for both liver and muscle. The intent is to define rigorously the phosphorylation sites critical to the physiological regulation of glycogen synthase by hormones and to probe the potential control of different glycogen synthase kinases. The several aims above are quite tightly interwoven conceptually, the unifying theme being to seek an unequivocal molecular basis for the control of glycogen synthase. Success would significantly extend knowledge of the mechanisms of action of several hormones, notably insulin, of obvious relevance to better understanding of situations of impaired insulin control such as in diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK027221-09
Application #
3228219
Study Section
Biochemistry Study Section (BIO)
Project Start
1979-11-01
Project End
1992-06-30
Budget Start
1987-07-01
Budget End
1988-06-30
Support Year
9
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Type
Schools of Medicine
DUNS #
005436803
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
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Irimia, Jose M; Meyer, Catalina M; Segvich, Dyann M et al. (2017) Lack of liver glycogen causes hepatic insulin resistance and steatosis in mice. J Biol Chem 292:10455-10464
Skurat, Alexander V; Segvich, Dyann M; DePaoli-Roach, Anna A et al. (2017) Novel method for detection of glycogen in cells. Glycobiology 27:416-424
Mahalingan, Krishna K; Baskaran, Sulochanadevi; DePaoli-Roach, Anna A et al. (2017) Redox Switch for the Inhibited State of Yeast Glycogen Synthase Mimics Regulation by Phosphorylation. Biochemistry 56:179-188
Contreras, Christopher J; Segvich, Dyann M; Mahalingan, Krishna et al. (2016) Incorporation of phosphate into glycogen by glycogen synthase. Arch Biochem Biophys 597:21-9
Scheffler, Tracy L; Park, Sungkwon; Roach, Peter J et al. (2016) Gain of function AMP-activated protein kinase ?3 mutation (AMPK?3R200Q) in pig muscle increases glycogen storage regardless of AMPK activation. Physiol Rep 4:
Ruchti, E; Roach, P J; DePaoli-Roach, A A et al. (2016) Protein targeting to glycogen is a master regulator of glycogen synthesis in astrocytes. IBRO Rep 1:46-53
Roach, Peter J (2015) Glycogen phosphorylation and Lafora disease. Mol Aspects Med 46:78-84
Irimia, Jose M; Tagliabracci, Vincent S; Meyer, Catalina M et al. (2015) Muscle glycogen remodeling and glycogen phosphate metabolism following exhaustive exercise of wild type and laforin knockout mice. J Biol Chem 290:22686-98
DePaoli-Roach, Anna A; Contreras, Christopher J; Segvich, Dyann M et al. (2015) Glycogen phosphomonoester distribution in mouse models of the progressive myoclonic epilepsy, Lafora disease. J Biol Chem 290:841-50

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