describe the principles of cell signalling using the example of the control of blood glucose concentration by glucagon, limited to: binding of hormone to cell surface receptor causing conformational change, activation of G-protein leading to stimulat

Homeostasis in Mammals – Control of Blood Glucose by Glucagon

Learning Objective

Describe the principles of cell signalling using the glucagon‑induced pathway that raises blood glucose concentration. Emphasise the sequence from hormone binding at the plasma membrane to activation of glycogen phosphorylase, and relate each step to the Cambridge International AS & A‑Level Biology syllabus (Topic 15 – Control & Coordination).

1. Hormone Classification & Release

• Glucagon – a peptide hormone stored in secretory granules of the pancreatic α‑cells.
• Released when blood glucose falls below ≈4 mmol L⁻¹ (e.g., fasting, exercise, stress).
• Acts on cells that express a specific G‑protein‑coupled receptor (GPCR) on their plasma membrane.

2. Key Concepts of Cell Signalling (Syllabus AO1)

• Signal transduction: conversion of an extracellular signal (hormone) into an intracellular response.
• Receptor type: 7‑transmembrane G‑protein‑coupled receptor (GPCR) – glucagon receptor.
• Second messenger: cyclic AMP (cAMP).
• Amplification: one hormone molecule can activate many G‑proteins; each G‑protein can stimulate many adenylyl‑cyclase (AC) enzymes; each active PKA can phosphorylate numerous downstream targets.
• Termination: phosphodiesterases (PDE) hydrolyse cAMP to AMP; protein phosphatases dephosphorylate kinases; receptor desensitisation.

3. Glucagon Signalling Cascade in Liver (Primary Target)

1. Hormone binding and receptor activation

   • Glucagon binds to the extracellular domain of the glucagon GPCR.
   • Binding induces a conformational change that exposes the intracellular binding site for the heterotrimeric G‑protein.

2. Activation of the heterotrimeric G‑protein (Gα_s)

   • In the inactive state the α‑subunit is bound to GDP.
   • Conformational change promotes exchange of GDP for GTP on the Gα_s subunit.
   • Gα_s-GTP dissociates from the βγ dimer and can interact with downstream effectors.

3. Stimulation of adenylyl cyclase (AC)

   • Gα_s-GTP binds to and activates membrane‑bound AC.
   • AC catalyses: ATP → cAMP + PPi.

4. cAMP as the second messenger

   • cAMP diffuses freely in the cytosol.
   • It binds to the regulatory subunits of protein kinase A (PKA), causing a conformational change that releases the catalytic subunits.

5. Activation of protein kinase A (PKA)

   • Free catalytic subunits phosphorylate several target proteins, the most important being phosphorylase kinase.

6. Phosphorylase kinase activation

   • Phosphorylation by PKA converts phosphorylase kinase to its active form.
   • In liver, Ca²⁺/calmodulin can further enhance activity, providing synergistic regulation during stress.

7. Glycogen phosphorylase activation

   • Active phosphorylase kinase phosphorylates glycogen phosphorylase (b → a form).
   • Glycogen phosphorylase catalyses glycogen phosphorolysis:

   Glycogenn + Pi ⟶glycogen phosphorylase Glycogenn‑1 + Glucose‑1‑P

   • Glucose‑1‑P is converted to glucose‑6‑P and then to free glucose, which is released into the bloodstream.

8. Signal termination

   • Phosphodiesterases hydrolyse cAMP to AMP, terminating PKA activation.
   • Protein phosphatases (e.g., PP1) dephosphorylate phosphorylase kinase and glycogen phosphorylase, returning them to the inactive state.
   • Receptor desensitisation (phosphorylation of the GPCR) reduces further G‑protein activation.

Allosteric Regulation of Glycogen Phosphorylase (AO2)

In addition to covalent phosphorylation, glycogen phosphorylase is modulated by small metabolites:

• Activators: AMP binds to the enzyme’s regulatory site, favouring the active “R” state.
• Inhibitors: ATP, glucose‑6‑P and glucose bind to allosteric sites, stabilising the inactive “T” state.

4. Other Target Tissues of Glucagon (AO1)

• Kidney – stimulates renal tubular re‑absorption of glucose, helping to conserve glucose during fasting.
• Adipose tissue – activates hormone‑sensitive lipase (via the same cAMP‑PKA cascade) → lipolysis → release of free fatty acids for hepatic β‑oxidation and gluconeogenesis.
• These actions complement hepatic glycogenolysis to raise blood glucose.

5. Comparison with the Antagonistic Insulin Pathway (RTK) – AO2

6. Feedback Regulation of Blood Glucose (AO2)

1. Low blood glucose → α‑cells release glucagon.
2. Glucagon stimulates hepatic glycogenolysis (and kidney re‑absorption, adipose lipolysis) → glucose released into blood.
3. Rising glucose stimulates β‑cells to secrete insulin.
4. Insulin activates the RTK‑PI3K‑Akt pathway, turning on glycogen synthase and glucose‑uptake mechanisms, thereby lowering blood glucose.

This negative‑feedback loop keeps blood glucose within a narrow physiological range (≈5 mmol L⁻¹).

7. Summary Table of the Glucagon Signalling Components

8. Key Points for Revision (Cambridge Syllabus)

• Glucagon → GPCR → Gα_s → AC → cAMP → PKA → phosphorylase kinase → glycogen phosphorylase.
• Each step provides amplification (many G‑proteins per hormone, many AC per G‑protein, many substrates per PKA).
• Signal termination is essential: phosphodiesterases convert cAMP to AMP; protein phosphatases reverse phosphorylation; GPCR desensitisation limits further signalling.
• Contrast with insulin, which uses a RTK → PI3K/Akt → glycogen synthase cascade – the classic antagonistic hormonal control of the same metabolic pathway.
• Allosteric regulators (AMP, ATP, glucose‑6‑P) fine‑tune glycogen phosphorylase activity, linking cellular energy status to the hormonal signal.
• Glucagon also acts on kidney (glucose re‑absorption) and adipose (lipolysis), ensuring a coordinated whole‑body response.
• Clinical relevance: glucagon emergency kits treat severe hypoglycaemia; drugs that block glucagon receptors (e.g., somatostatin analogues) are used in certain metabolic disorders.