A 24-year-old man with type 1 diabetes mellitus is brought to the emergency department unconscious by his roommate. The roommate found him unresponsive and administered an intramuscular injection of glucagon prior to arrival. Upon evaluation, the patient is regaining consciousness, and his capillary blood glucose is now mg/dL (reference range: - mg/dL), up from an unrecorded low value at home.
Arrange the following sequence of molecular events that occurred in this patient's hepatocytes in response to the emergency intramuscular injection, ultimately leading to the restoration of his serum glucose levels.
- 1Conformational change of the cell surface receptor and dissociation of the Gs-alpha protein subunit
- 2Activation of adenylate cyclase and generation of the second messenger cyclic AMP (cAMP)
- 3Binding of cAMP to regulatory subunits and release of active Protein Kinase A (PKA) catalytic subunits
- 4Phosphorylation and activation of the intermediate enzyme phosphorylase kinase
- 5Phosphorylation of glycogen phosphorylase to its active state to initiate glycogenolysis
Answer
The correct physiological sequence following glucagon administration is: GPCR activation causing Gs-alpha dissociation, followed by adenylate cyclase activation producing cAMP, which then activates PKA. PKA phosphorylates phosphorylase kinase, which in turn phosphorylates and activates glycogen phosphorylase to initiate glycogen breakdown.
The glucagon signaling cascade is a classic example of Gs-protein coupled receptor signaling. In response to severe hypoglycemia, administered glucagon binds to its GPCR on hepatocytes. This binding causes a conformational change that induces the Gs-alpha subunit to exchange GDP for GTP and dissociate. The free Gs-alpha subunit activates the membrane-bound enzyme adenylate cyclase, which rapidly converts intracellular ATP into the second messenger cAMP. The rising levels of cAMP bind to the regulatory subunits of Protein Kinase A (PKA), causing them to release the active catalytic subunits. To massively amplify the signal, active PKA first phosphorylates an intermediate enzyme, phosphorylase kinase, turning it on. This active phosphorylase kinase then phosphorylates the key rate-limiting enzyme, glycogen phosphorylase (converting it from inactive form b to active form a). Active glycogen phosphorylase immediately begins cleaving 1,4-glycosidic bonds in glycogen to release glucose-1-phosphate, which is subsequently converted to free glucose and exported into the blood to rescue the patient from hypoglycemia.
Step-by-Step Solution
Key Concept
The intracellular signaling cascade for glucagon relies on a Gs-coupled receptor, adenylate cyclase, cAMP, and Protein Kinase A to ultimately activate glycogen phosphorylase via an amplifying kinase cascade.