Regulation of Glycogen Metabolism PDF

REGULATION OF GLYCOGEN SYNTHESIS AND DEGRADATION In the liver: – well fed: glycogenesis – Fasting: glycogenolysis In muscle: – active exercise: glycogenolysis – At rest: glycogenesis Regulation: by glycogen phosphorylase – Allosteric regulation – hormonally regulated synthase and glycogen Regulation...

REGULATION OF GLYCOGEN SYNTHESIS AND DEGRADATION In the liver: – well fed: glycogenesis – Fasting: glycogenolysis In muscle: – active exercise: glycogenolysis – At rest: glycogenesis Regulation: by glycogen phosphorylase – Allosteric regulation – hormonally regulated synthase and glycogen Regulation of Glycogen Synthesis and Degradation in Skeletal Muscle The regulation of glycogenolysis in skeletal muscle is related to the availability of ATP for muscular contraction. Glucose 1-phosphate is converted to glucose 6phosphate, which is committed to the glycolytic pathway The regulation of skeletal muscle glycogen degradation therefore must respond very rapidly to the need for ATP, indicated by the increase in AMP. Muscle Phosphorylase Glycogen phosphorylase of skeletal muscle exists in two interconvertible forms: – phosphorylase a : catalytically active – phosphorylase b : less active In muscle : high concentrations of AMP : allosteric activator high concentrations of ATP: allosteric inhibitor Epinephrine: activates phosphorylase a Phosphorylase a & b Phosphorylase exists in an a form, which is active, and b form, which is inactive. These forms are interconverted by the actions of phosphorylase kinase and phosphoprotein phosphatase “a” has covalent P in “b” P is absent Glucogon/Epinephrine signaling pathway – Starts phosphorylation cascade via cAMP – activates glycogen phosphorylase Glycogen phosphorylase cleaves glucose residues off glycogen, generating glucose-1-phosphate In resting muscle, nearly all the enzyme is in the inactive b form. When exercising, the elevated level of AMP leads to the activation of phosphorylase Exercise will also result in hormone release that generates the phosphorylated a form of the enzyme Glycogen phosphorylase generates glucose-1phosphate which is isomerized into glucose-6phosphate and enters the glycolytic pathway to produce ATP. This end product ATP is a feed back inhibitor of glycogen phosphorylase. Glucose-6-phosphate is an allosteric inhibitor of the enzyme Role of Calcium The activation of the calcium/calmodulin subunit of phosphorylase kinase by the Ca released from the sarcoplasmic reticulum during muscle contraction provides a direct and rapid means of stimulating glycogen degradation. Liver Phosphorylase Produces glucose for use by other tissues The action of phosphorylase is sensitive to the presence of glucose: – the binding of glucose deactivates the enzyme The important point is that hormones that increase cAMP levels, such as glucagon and epinephrine, promote activation of glycogen phosphorylase by signaling activation of phosphorylase kinase and inactivation of phosphoprotein phosphatase. On the other hand, insulin, which acts either though a second messenger or a kinase mediated signal cascade, exerts the opposite effect on phosphorylase by promoting activation of phosphoprotein phosphatase activity. Pathway Integration: Hormonal control of glycogen breakdown; Glucagon stimulates liver glycogen breakdown when blood glucose is low. Epinephrine enhances glycogen breakdown in muscle and the liver to provide fuel for muscle contraction. The regulation of skeletal muscle glycogen synthesis and degradation differs from that in liver in several important respects: a) Glucagon has no effect on muscle, and thus glycogen levels in muscle do not vary with the fasting/feeding state b) AMP is an allosteric activator of the muscle isozyme of glycogen phosphorylase, but not liver glycogen phosphorylase c) The effects of Ca in muscle result principally from the release of Ca from the sarcoplasmic reticulum after neural stimulation and not from epinephrine-stimulated uptake d) The effects of epinephrine-stimulated phosphorylation by protein kinase A on skeletal muscle glycogen degradation and glycogen synthesis are similar to those occurring in liver Glycogen breakdown must be rapidly turned off when necessary The signal-transduction pathway leading to the activation of glycogen phosphorylase is shut down automatically when the initiating hormone is no longer present Regulation of Glycogen Synthase Allosteric regulation – Glycogen synthase is stimulated by ATP and glucose-6-P Hormonal control (by covalent modification) : – Glycogen synthase is phosphorylated at multiple sites by several protein kinases, notably protein kinase A and glycogen synthase kinase (GSK) Phosphorylation converts the active a form of the synthase into a usually inactive b form. Allosteric regulation of glycogen synthesis and degradation Glycogen Breakdown and Synthesis Are Reciprocally Regulated The same glucagon- and epinephrine-triggered cAMP cascades that initiate glycogen breahdown in the liver and muscle, respectively, also shut off glycogen synthesis. Insulin Stimulates Glycogen Synthesis by inactivating Glycogen Synthase Kinase (GSK) Insulin blocks the the activity of GSK-3 Glycogen synthase is controlled by phosphorylation Insulin blocks the activity of GSK-3 and triggers activation of glycogen synthase Insulin activates Protein phosphatase 1 ( PP1) How is the enzymatic activity reversed so that glycogen breakdown halts and glycogen synthesis begins? Protein phosphatase 1 (PP1) plays key roles in regulating glycogen metabolism PP1 catalyzes –dephosphorylation – PP1 inactivates gylcogen phosphorylase – PP1 also removes phosphoryl groups from glycogen synthase b to convert it into the much more active glycogen synthase a form. Elevated insulin – triggers increased glycogen synthesis in myocytes by activating PP1 and inactivating GSK3. – Unlike hepatocytes, myocytes have a reserve of GLUT4 sequestered in intracellular vesicles. Insulin triggers their movement to the plasma membrane, where they allow increased glucose uptake. – In response to insulin, therefore, myocytes help to lower blood glucose by increasing their rates of glucose uptake, glycogen synthesis, and glycolysis. Control of Carbohydrate Metabolism in the Liver vs. the Muscle 1. Muscle uses its stored glycogen only for its own needs 2. As it goes from rest to vigorous contraction, muscle undergoes very large changes in its demand for ATP, which is supported by glycolysis 3. Muscle lacks the enzymatic machinery for gluconeogenesis Control of Carbohydrate Metabolism in the Liver vs. the Muscle Control of Carbohydrate Metabolism in the Liver