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 – Control of Blood Glucose

Physiological Context

• Set‑point: Blood glucose is normally maintained at ≈4–6 mmol L⁻¹.
• When is glucagon released? During fasting or between meals when plasma glucose falls below ~4 mmol L⁻¹.
• Source organ: α‑cells of the pancreatic islets.
• Primary target organ: Liver (hepatocytes) – the main site of glycogen storage and gluconeogenesis.
• Antagonistic hormone: Insulin, released from β‑cells when glucose is high, lowers blood glucose. The two hormones act in opposition to keep glucose within the narrow set‑point.

Glucagon Signalling Pathway (GPCR → cAMP)

Step‑by‑step cascade

1. Hormone binding & receptor conformational change

   • Glucagon binds to a specific 7‑transmembrane G‑protein‑coupled receptor (GPCR) on the hepatocyte plasma membrane.
   • The binding induces an induced‑fit change that exposes the intracellular G‑protein‑binding site.

2. Activation of the heterotrimeric G‑protein

   • The GPCR acts as a guanine‑nucleotide‑exchange factor (GEF), replacing GDP with GTP on the α‑subunit (Gα).
   • Gα‑GTP dissociates from the βγ‑dimer; both Gα‑GTP and βγ can modulate downstream effectors (for glucagon the α‑subunit is the key activator).

3. Stimulation of adenylyl cyclase (AC)

   • Gα‑GTP binds to and activates membrane‑bound AC.
   • Active AC catalyses the conversion of ATP → cyclic AMP (cAMP).

4. Second‑messenger accumulation

   • cAMP diffuses through the cytosol and binds to the regulatory (R) subunits of protein kinase A (PKA).
   • Binding releases the catalytic (C) subunits, generating active PKA.

5. Phosphorylation cascade

   • Active PKA phosphorylates phosphorylase kinase, converting it to the active form.
   • Phosphorylase kinase then phosphorylates glycogen phosphorylase a, the enzyme that cleaves glycogen to glucose‑1‑phosphate.

6. Metabolic response – glycogenolysis

   • Glucose‑1‑phosphate is rapidly converted to glucose‑6‑phosphate and, via glucose‑6‑phosphatase, released as free glucose into the bloodstream.
   • Result: ↑ blood glucose concentration.

7. Additional glucagon‑driven processes (brief)

   • Gluconeogenesis: cAMP‑PKA up‑regulates transcription of PEPCK and glucose‑6‑phosphatase, providing a non‑carbohydrate source of glucose.
   • Lipolysis & ketogenesis: In adipose tissue, glucagon (via the same cAMP pathway) activates hormone‑sensitive lipase, releasing fatty acids that the liver converts to ketone bodies.

Signal Amplification

Each activated PKA catalytic subunit can phosphorylate dozens of phosphorylase‑kinase molecules; each phosphorylase‑kinase can activate many glycogen‑phosphorylase enzymes. This hierarchical amplification produces a large metabolic output from a single glucagon‑receptor interaction.

Regulation of the Glucagon Cascade

• Phosphodiesterases (PDEs): Hydrolyse cAMP to AMP, terminating the second‑messenger signal.
• Protein phosphatases: Protein phosphatase‑1 (PP1) de‑phosphorylates phosphorylase‑kinase and glycogen phosphorylase a, switching the pathway off.
• Receptor desensitisation: Prolonged glucagon exposure leads to GPCR phosphorylation by GRKs and β‑arrestin binding, reducing G‑protein coupling.
• Negative feedback by glucose: Rising plasma glucose suppresses further glucagon release from α‑cells.
• Insulin antagonism: Insulin activates PP1 and stimulates glycogen synthase, driving glucose back into storage.

Insulin Signalling (Overview – Tyrosine‑Kinase Receptor)

• Hormone binding: Insulin binds to its receptor (a receptor tyrosine kinase) on muscle, adipose and liver cells.
• Receptor autophosphorylation: Intracellular tyrosine residues are phosphorylated, creating docking sites for IRS proteins.
• PI3K‑Akt pathway: IRS recruits phosphoinositide‑3‑kinase (PI3K), generating PIP₃, which activates Akt (PKB).
• Key cellular responses:

  • Akt phosphorylates and inactivates glycogen synthase kinase‑3 (GSK‑3), allowing glycogen synthase to become active → glycogen synthesis.
  • Akt stimulates translocation of GLUT4 vesicles to the plasma membrane → ↑ glucose uptake.
  • Akt activates protein phosphatase‑1, de‑phosphorylating glycogen phosphorylase a → ↓ glycogenolysis.

• Overall effect: Blood glucose is lowered, complementing the glucagon response.

Quantitative Example (AO2)

Basal adenylyl cyclase activity in a hepatocyte = 0.5 µmol cAMP min⁻¹ mg⁻¹ protein. Glucagon binding increases the enzyme’s V_max five‑fold.

• New activity = 0.5 µmol × 5 = 2.5 µmol cAMP min⁻¹ mg⁻¹.
• If the cell contains 2 mg of protein, total cAMP produced per minute rises from 1.0 µmol to 5.0 µmol – a 5‑fold increase.
• This rise is sufficient to occupy ≈80 % of PKA regulatory sites (when [cAMP] > K_d), ensuring maximal catalytic activity.

The calculation links hormone concentration, enzyme kinetics and the magnitude of the cellular response – a typical AO2 requirement.

Summary Table

Suggested Diagram

Flowchart (or labelled schematic) showing: glucagon → GPCR (induced‑fit) → Gα‑GTP → adenylyl cyclase → ↑cAMP → PKA activation → phosphorylase kinase → glycogen phosphorylase a → glucose release. Include side boxes for gluconeogenesis, lipolysis, and a brief inset of the insulin‑tyrosine‑kinase pathway for contrast.