Glycogen Metabolism Regulation

Regulation of Glycogen Metabolism

• Glycogen synthase has active and inactive forms in synthesis.
• Glycogen phosphorylase has active and inactive forms in degradation.
• Regulation occurs allosterically and hormonally.
• Glycogen synthesis is stimulated when energy levels and substrate availability are high.
• Glycogen degradation increases when energy levels are low.
• ATP blocks the allosteric site to which AMP binds and inactivates glycogen synthase when energy levels are adequate and glucose supplies are available.

Hormonal Regulation of Glycogen Synthesis

• High glucose concentrations stimulate the pancreas.
• Insulin is released into the bloodstream as a result of the stimulation.
• Glucagon release is simultaneously stopped.
• Glycogen synthase activation is tightly linked to glycogen phosphorylase inhibition.
• Glycogen synthase is active in its dephosphorylated form.
• It responds to hormonal action in the presence of insulin.
• Dephosphorylation occurs via protein phosphatase.
• Glycogen phosphorylase is inactive in its dephosphorylated form, leading to no glycogen breakdown.
• Glycogen phosphorylase is active, and glycogen synthase is inactive in the presence of glucagon.

Hormonal Regulation and cAMP

• Cyclic AMP (cAMP) forms from ATP via adenyl cyclase on the inner surface of cell membranes.
• Cyclic AMP acts as an intracellular second messenger
• It responds to hormones like epinephrine, norepinephrine, and glucagon.
• cAMP is hydrolyzed by phosphodiesterase, which terminates hormone action.
• In the liver, insulin increases the activity of phosphodiesterase.
• Glucagon and epinephrine activate G-protein coupled receptors to trigger cAMP cascades.
• Both hormones are produced in response to low blood sugar.
• Glucagon, from α-cells of the pancreas, activates cAMP formation in the liver.
• Epinephrine activates cAMP formation in muscle.

cAMP Cascade Effects

• The cAMP cascade phosphorylates a serine hydroxyl of Glycogen Phosphorylase.
• This phosphorylation promotes transition to the active (relaxed) state.
• The phosphorylated enzyme becomes less sensitive to allosteric inhibitors.
• Phosphorylase will be active even if cellular ATP & glucose-6-phosphate are high.
• Glucose-1-phosphate produced from glycogen in the liver can be converted to free glucose for release into the blood.
• Organism needs take precedence over cell needs with hormone-activated regulation.
• The cAMP cascade has the opposite effect on glycogen synthesis as induced by glucagon or epinephrine in the liver.
• Glycogen Synthase is phosphorylated by Protein Kinase A and Phosphorylase Kinase.
• Phosphorylation of Glycogen Synthase promotes the "b" (less active) conformation.
• The cAMP cascade inhibits glycogen synthesis.
• Glucose-1-P in the liver can be converted to glucose-6-P and dephosphorylated for release to the blood instead of being converted to glycogen.

Insulin and Phosphoprotein Phosphatase

• Insulin is produced in response to high blood glucose.
• Insulin triggers a separate signal cascade which activates Phosphoprotein Phosphatase.
• This phosphatase removes regulatory phosphate residues from Phosphorylase, Phosphorylase Kinase, and Glycogen Synthase enzymes.
• Insulin antagonizes the effects of the cAMP cascade induced by glucagon and epinephrine.

Glycogen Degradation

• Blood glucose drops, or energy demand increases in response to glucagon or epinephrine.
• Glycogen phosphorylase activity increases to provide glucose.
• Glycogen Phosphorylase is a homodimeric enzyme subject to allosteric control.
• It transitions between “relaxed” (active) & “tense” (inhibited) conformations.
• Inhibitors bind at the dimer interface, stabilizing the inactive (tense) conformation.
• Glycogen Phosphorylase in muscle is subject to allosteric regulation by AMP, ATP, and glucose-6-phosphate.
• A separate isozyme of Phosphorylase expressed in the liver is less sensitive to allosteric controls.
• AMP (present significantly when ATP is depleted) activates Phosphorylase
• This promotes the relaxed conformation.
• ATP & glucose-6-phosphate have binding sites that overlap that of AMP
• ATP & glucose-6-phosphate inhibit Phosphorylase, promoting the tense conformation.
• When ATP and glucose-6-phosphate are plentiful, glycogen breakdown is inhibited.

Glycogen Synthase and Glucose-6-P

• Glycogen Synthase is allosterically activated by glucose-6-P (opposite of effect on Phosphorylase).
• Glycogen Synthase is active when high blood glucose leads to elevated intracellular glucose-6-P.
• It is useful to store glucose as glycogen when the input to Glycolysis (glucose-6-P) and the main product of Glycolysis (ATP) are adequate.
• High cytosolic glucose-6-phosphate, resulting from high blood glucose, turns off the signal for glycogen synthesis.
• The conformation of Glycogen Synthase induced by the allosteric activator glucose-6-phosphate becomes susceptible to dephosphorylation by Protein Phosphatase.

Role of Ca2+

• There is a rapid and urgent need for ATP during muscle contraction.
• This energy is supplied by muscle glycogen stores.
• Nerve impulses cause membrane depolarization
• Ca2+ is released from the sarcoplasmic reticulum into the sarcoplasm of myocytes as a result.
• Ca2+ activates muscle phosphorylase kinase b by binding to the calmodulin component (CaM subunit) of phosphorylase kinase.
• Ca++ regulates glycogen breakdown in muscle.
• Phosphorylase Kinase is partly activated by binding of Ca++ to its subunit.
• During extended exercise, as glycogen stores deplete, muscle cells rely more on glucose uptake from the blood
• They also rely fatty acid catabolism as a source of ATP.
• Phosphorylation of the enzyme, via a cAMP cascade induced by epinephrine, further activates it.
• These regulatory processes ensure the release of phosphorylated glucose from glycogen for entry into Glycolysis for ATP production in muscle contraction.

Control in Liver Cells

• Control in liver cells includes reciprocal effects (on glycolysis and gluconeogenesis) of a cyclic AMP cascade, triggered by glucagon when blood glucose is low.
• Phosphorylation of enzymes & regulatory proteins in the liver by Protein Kinase A result in: inhibition of glycolysis and stimulation of gluconeogenesis.
• Liver creates glucose to the available to the blood.

Effects of glucagon-cAMP cascade in the Liver

• Gluconeogenesis, glycogen breakdown stimulated.
• Glycolysis and glycogen synthesis is inhibited.
• Free glucose is formed for release into the blood.