Organizing glucose disposal: emerging roles of the glycogen targeting subunits of protein phosphatase-1.
Glucose is stored in mammalian tissues in the form of glycogen. Glycogen levels are markedly reduced in liver or muscle cells of patients with insulin-resistant or insulin-deficient forms of diabetes, suggesting that impaired glycogen synthesis may contribute to development of hyperglycemia. Recently, interest in this area has been further stimulated by new insights into the spatial organization of metabolic enzymes within cells and the importance of such organization in regulation of glycogen metabolism. It is now clear that a four-member family of glycogen targeting subunits of protein phosphatase-1 (PP1) plays a major role in coordinating these events. These proteins target PP1 to the glycogen particle and also bind differentially to glycogen synthase, glycogen phosphorylase, and phosphorylase kinase, thereby serving as molecular scaffolds. Moreover, the various glycogen-targeting subunits have distinct tissue expression patterns and can influence regulation of glycogen metabolism in response to glycogenic and glycogenolytic signals. The purpose of this article is to summarize new insights into the structure, function, regulation, and metabolic effects of the glycogen-targeting subunits of PP1 and to evaluate the possibility that these molecules could serve as therapeutic targets for lowering of blood glucose in diabetes.
Newgard
C B
CB
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas 75235, USA. newgard@utsw.swmed.edu
Brady
M J
MJ
O'Doherty
R M
RM
Saltiel
A R
AR
D000818:Animals; D003920:Diabetes Mellitus / Q000188:drug therapy; D005947:Glucose / Q000378:metabolism*; D006003:Glycogen / Q000378:metabolism; D006801:Humans; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D054645:Protein Phosphatase 1; D013329:Structure-Activity Relationship
D020033:Protein Isoforms; D006003:Glycogen; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D005947:Glucose