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

Published by Patrick Mutisya · 14 days ago

Homeostasis in Mammals – Glucagon Signalling Pathway

Homeostasis in Mammals – Control of Blood Glucose by Glucagon

Objective

Describe the principles of cell signalling using the glucagon‑induced pathway that lowers blood glucose concentration. Focus on the sequence from hormone binding to the final activation of glycogen phosphorylase.

Key Steps in the Glucagon Signalling Cascade

  1. Hormone binding and receptor activation

    Glucagon, a peptide hormone, binds to a specific G‑protein‑coupled receptor (GPCR) on the plasma membrane of liver cells. Binding induces a conformational change in the receptor that allows interaction with the heterotrimeric G‑protein.

  2. Activation of the G‑protein

    The intracellular G‑protein (composed of α, β, γ subunits) exchanges GDP for GTP on its α‑subunit, causing dissociation of the α‑GTP from the βγ dimer.

  3. Stimulation of adenylyl cyclase

    The activated α‑GTP subunit binds to and stimulates adenylyl cyclase (AC), an integral membrane enzyme.

  4. Formation of the second messenger – cyclic AMP (cAMP)

    AC catalyses the conversion of ATP to cyclic AMP:

    \$cAMP = ATP \xrightarrow{\text{adenylyl cyclase}} cAMP + PP_i\$

    cAMP diffuses freely in the cytosol and serves as the second messenger.

  5. Activation of protein kinase A (PKA)

    cAMP binds to the regulatory subunits of PKA, causing them to release the catalytic subunits. The free catalytic subunits are now active.

  6. Initiation of an enzyme cascade (phosphorylation cascade)

    The catalytic subunits of PKA phosphorylate target enzymes, most notably phosphorylase kinase.

  7. Signal amplification

    Each activated PKA molecule can phosphorylate many molecules of phosphorylase kinase; each phosphorylated phosphorylase kinase can in turn phosphorylate multiple molecules of glycogen phosphorylase. This cascade results in exponential amplification of the original signal.

  8. Cellular response – glycogen breakdown

    The final enzyme, glycogen phosphorylase, when phosphorylated, becomes active and catalyses the phosphorolysis of glycogen:

    \$\text{Glycogen}{(n)} + Pi \xrightarrow{\text{glycogen phosphorylase}} \text{Glycogen}_{(n-1)} + \text{Glucose‑1‑P}\$

    The released glucose‑1‑phosphate is converted to glucose‑6‑phosphate and ultimately to free glucose, raising blood glucose levels.

Summary Table of the Signalling Components

StepMolecule InvolvedActionResult
1Glucagon + GPCRLigand binding → receptor conformational changeReceptor ready to activate G‑protein
2G‑protein (α subunit)GDP → GTP exchangeα‑GTP dissociates and activates AC
3Adenylyl cyclaseConversion of ATP to cAMPSecond messenger generated
4cAMPBinds PKA regulatory subunitsPKA catalytic subunits released
5Protein kinase A (PKA)Phosphorylates phosphorylase kinasePhosphorylase kinase activated
6Phosphorylase kinasePhosphorylates glycogen phosphorylaseGlycogen phosphorylase active
7Glycogen phosphorylaseCatalyses glycogen → glucose‑1‑PGlucose released into blood

Suggested diagram: Schematic of the glucagon‑triggered G‑protein‑cAMP‑PKA signalling pathway leading to glycogen breakdown.

Key Points for Revision

  • Glucagon acts through a GPCR, not a nuclear receptor.

  • cAMP is the classic second messenger for many hormone pathways.

  • Protein kinases amplify signals by phosphorylating multiple downstream targets.

  • The cascade is reversible; phosphatases deactivate the enzymes to terminate the response.

  • Understanding each step helps explain how drugs that mimic or block glucagon can affect blood glucose regulation.