Hormonal control of glycogen breakdown: how do glucagon and epinephrine stimulate glycogen phosphorylase to generate G-1-P (and hence G-6-P) from glycogen?

Difficulty: Easy

Correct Answer: Indirectly, by first stimulating adenylate cyclase to make cAMP

Explanation:


Introduction / Context:
Glycogenolysis is hormonally regulated to mobilize glucose during fasting or acute stress. This question probes the signaling mechanism by which glucagon (liver-focused) and epinephrine (liver and muscle) activate glycogen breakdown.


Given Data / Assumptions:

  • Hormones bind cell-surface G protein–coupled receptors.
  • Glycogen phosphorylase releases glucose-1-phosphate (G-1-P) from glycogen using inorganic phosphate (Pi).
  • Signal amplification cascades are typical in these pathways.


Concept / Approach:
Glucagon and epinephrine activate Gs-coupled receptors, which stimulate adenylate cyclase to produce cAMP. cAMP activates protein kinase A (PKA), which phosphorylates phosphorylase kinase; phosphorylase kinase then activates glycogen phosphorylase by phosphorylation, increasing glycogen breakdown. G-1-P is converted to G-6-P by phosphoglucomutase.


Step-by-Step Solution:
1) Hormone binds GPCR → Gs activates adenylate cyclase.2) Adenylate cyclase converts ATP to cAMP.3) cAMP activates PKA, which phosphorylates phosphorylase kinase.4) Phosphorylase kinase phosphorylates glycogen phosphorylase (b → a), stimulating glycogenolysis.5) G-1-P is produced and then isomerized to G-6-P.


Verification / Alternative check:
Classic experiments show that cAMP analogs mimic hormonal effects and that PKA inhibitors block glycogen phosphorylase activation, confirming the indirect cAMP-mediated mechanism.


Why Other Options Are Wrong:
Option A: Epinephrine acts in muscle as well as liver. Option B: The phosphoryl donor at glycogen phosphorylase is inorganic phosphate (Pi), not ATP. Option C: Hormones do not bind the enzyme directly; activation is via signaling. Option E: Flux is not driven by inhibiting phosphoglucomutase; its role is downstream isomerization.


Common Pitfalls:
Assuming ATP donates phosphate directly in the catalytic step of glycogen phosphorylase, or overlooking the layered kinase cascade initiated by cAMP.


Final Answer:
Indirectly, by first stimulating adenylate cyclase to make cAMP

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