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?

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