Hormones and cAMP
Global coordination of glucose utilization and glycogen metabolism is regulated by circulating hormones, including the pancreatic hormones insulin (secreted by
b cells) and glucagon (secreted by a cells), and the adrenal hormone epinephrine.Insulin secretion is stimulated by:
1. High levels of blood glucose (after a carbohydrate-rich meal)
2. High levels of amino acids in plasma (after a protein-rich meal)
3. Gastrointestinal hormones (e.g. secretin), stimulating an anticipatory rise in insulin
after a meal, even before blood glucose level increases
4. Glucagon
Insulin secretion is inhibited by epinephrine.
Glucagon secretion is stimulated by:
1. Low levels of blood glucose (fasting)
2. High levels of amino acids in plasma (after a protein-rich meal)
3. Epinephrine
Glucagon secretion is inhibited by insulin and high glucose levels.
Epinephrine overrides the effects of blood glucose on both insulin and glucagon secretion.
Glucagon receptor signaling
Binding of glucagon to a cell-surface receptor initiates a signal transduction cascade that results in phosphorylation of multiple enzymes involved in carbohydrate metabolism. Phosphorylation may activate or inhibit a target enzyme.
Glycolysis:
phosphofructokinase 2 is INHIBITED
fructose bisphosphatase 2 is ACTIVATED
... F-2,6-BP is destroyed, glycolysis is slowed
pyruvate kinase is INHIBITED
... glycolysis is slowed
Glycogen metabolism:
glycogen synthase is INHIBITED
... glycogen synthesis is slowed
glycogen phosphorylase is ACTIVATED
... glycogen breakdown is speeded up
Adenylyl cyclase is a membrane-bound enzyme that synthesizes cyclic AMP (cAMP) in an irreversible reaction. cAMP is hydrolyzed to AMP by phosphodiesterase.
cAMP activates the enzyme cyclic-AMP-dependent protein kinase, also known as protein kinase A or A-kinase. Inactive A-kinase catalytic subunits are held in a complex by regulatory subunits. Binding of cAMP to the regulatory subunits allows the catalytic subunits to dissociate from the complex, and phosphorylate its targets on specific serine and threonine residues..
A-kinase directly phosphorylates glycogen synthase. Phosphorylated glycogen synthase is inactive, so glucagon inhibits glycogen synthesis.
A-kinase activates glycogen phosphorylase by a two-step mechanism, increasing the rate of glycogen breakdown.
Phosphate groups on serine and threonine are rapidly removed by protein phosphatases. In muscle cells stimulated by epinephrine, protein phosphatase-I is inhibited indirectly. This prolongs the response of glycogen metabolism to hormonal stimulation.
Summary of cAMP-mediated effects on glycogen metabolism:
Further effects of epinephrine
In addition to stimulating adenylyl cyclase to produce cyclic AMP via
b-adrenergic receptors, epinephrine induces the release of intracellular calcium, mediated by a-adrenergic receptors. a-adrenergic receptors activate the enzyme phospholipase C, which cleaves the membrane lipid PIP2 to generate diacylglycerol and IP3.
IP3 stimulates the release of calcium from intracellular membrane-bound stores, the endoplasmic reticulum in most cells or sarcoplasmic reticulum in muscle. Calcium ions in the cytoplasm bind to the ubiquitous small protein calmodulin, inducing a profound conformational change.
Calcium-bound calmodulin is a stimulatory subunit of phosphorylase kinase. This calcium-dependent activation of phosphorylase kinase is synergistic with the stimulation induced by cAMP-dependent protein kinase (A-kinase). Calcium is also released during muscle contraction, so this mechanisms couples glycogen breakdown to exertion.
