Biochemistry chapters
Hormone receptors and signal transduction
How hormones carry messages: classification by chemistry and receptor site, cell-surface versus intracellular receptors, the second messenger systems (cAMP, IP3/DAG/calcium, cGMP), tyrosine kinase and JAK-STAT pathways, signal ending, and diseases and toxins that disturb signalling (cholera, pertussis, Gs mutations).
- Group I hormones (lipophilic: steroids, thyroid hormones, calcitriol, retinoic acid) cross the membrane, bind intracellular (nuclear) receptors that act on hormone response elements in DNA (slow, long-lasting); group II hormones (water-soluble peptides and catecholamines) bind cell-surface receptors and act through second messengers (fast).
- G protein-coupled receptors: Gs activates adenylyl cyclase → cAMP → protein kinase A (glucagon, β receptors, TSH, ACTH, LH, FSH, PTH, ADH-V2); Gi inhibits it (α2, M2); Gq activates phospholipase C → IP3 (calcium release) + DAG (protein kinase C) (α1, M1, M3, ADH-V1, oxytocin, GnRH, TRH, angiotensin II); cAMP is broken down by phosphodiesterase (blocked by theophylline and caffeine).
- Receptor tyrosine kinases (insulin, IGF-1, growth factors) autophosphorylate; JAK-STAT receptors serve growth hormone, prolactin, erythropoietin and cytokines; cGMP mediates nitric oxide and ANP; cholera toxin locks Gs on (watery diarrhoea), pertussis toxin locks Gi off.
On this page
Classification of hormones
By chemistry
| Class | Examples | Features |
|---|---|---|
| Peptides and proteins | Insulin, glucagon, GH, ACTH, PTH, ADH, oxytocin | Water-soluble; stored in granules; cell-surface receptors |
| Steroids (from cholesterol) | Cortisol, aldosterone, sex hormones, calcitriol | Lipid-soluble; made on demand; carried on proteins; intracellular receptors |
| Amines (from tyrosine or tryptophan) | Catecholamines (surface receptors), thyroid hormones (intracellular receptors), melatonin | Mixed behaviour |
| Eicosanoids | Prostaglandins, leukotrienes | Local action |
By receptor location
| Feature | Group I: intracellular receptors | Group II: cell-surface receptors |
|---|---|---|
| Hormones | Steroids, thyroid hormones, calcitriol, retinoic acid | Peptides, proteins, catecholamines |
| Solubility | Lipophilic; cross membranes | Hydrophilic; cannot cross |
| Transport in blood | Bound to carrier proteins (long half-life) | Mostly free (short half-life) |
| Mechanism | Hormone-receptor complex binds hormone response elements (HREs) in DNA → gene transcription | Second messengers or kinase cascades |
| Speed | Hours to days | Seconds to minutes |
Thyroid hormone (T3) receptors sit in the nucleus already bound to DNA; steroid receptors (for example the glucocorticoid receptor) are in the cytoplasm bound to heat shock proteins and move to the nucleus after binding.
Second messenger systems
1. cAMP pathway (Gs and Gi)
Hormone → receptor → Gs protein (GTP-bound α subunit) → activates adenylyl cyclase → ATP → cAMP → activates protein kinase A → phosphorylates target proteins.
- Gs-linked: glucagon, adrenaline (β1, β2), TSH, ACTH, LH, FSH, PTH, ADH (V2, kidney), hCG, calcitonin, CRH, GHRH, histamine (H2), dopamine (D1).
- Gi-linked: inhibits adenylyl cyclase: α2, M2, D2, somatostatin, opioids.
Ending the signal: Gα has GTPase activity (turns itself off); phosphodiesterase breaks down cAMP (inhibited by theophylline, caffeine: more cAMP).
2. Phosphatidylinositol pathway (Gq)
Hormone → receptor → Gq → activates phospholipase C → splits PIP2 into:
- IP3 → releases calcium from the endoplasmic reticulum → calcium-calmodulin activates kinases (smooth muscle contraction via myosin light chain kinase).
- DAG → activates protein kinase C.
Gq-linked: α1, M1, M3, ADH (V1, blood vessels), oxytocin, GnRH, TRH, angiotensin II, histamine (H1), gastrin, CCK.
3. cGMP pathway
- Soluble guanylyl cyclase: activated by nitric oxide (from endothelium; nitrates) → cGMP → vascular smooth muscle relaxation.
- Membrane guanylyl cyclase receptors: ANP, BNP.
- cGMP broken down by phosphodiesterase 5 (blocked by sildenafil).
4. Receptor tyrosine kinases
The receptor itself is an enzyme: hormone binding → dimerisation and autophosphorylation of tyrosines → docking proteins → cascades (PI3 kinase/Akt, Ras/MAP kinase).
- Insulin (receptor is a pre-formed dimer; IRS-1 docking protein; GLUT4 translocation through PI3K), IGF-1, EGF, PDGF, FGF.
5. JAK-STAT (cytokine receptors)
The receptor has no enzyme activity; it recruits JAK (Janus kinase), which phosphorylates STAT proteins that move to the nucleus.
- Growth hormone, prolactin, erythropoietin, leptin, interferons, many interleukins, G-CSF.
- Targets: JAK inhibitors (tofacitinib, ruxolitinib); JAK2 mutation in polycythaemia vera.
Glucagon, PTH, TSH, ACTH, LH, FSH, ADH-V2 → cAMP (Gs). Oxytocin, GnRH, TRH, ADH-V1, angiotensin II → IP3/Ca (Gq). Insulin → tyrosine kinase. GH, prolactin, EPO → JAK-STAT. NO, ANP → cGMP. Steroids, thyroid, vitamin D → nuclear receptors.
Disorders of signalling
| Condition | Defect |
|---|---|
| Cholera | Cholera toxin ADP-ribosylates Gsα, keeping it permanently active → ↑ cAMP in gut cells → CFTR chloride secretion → profuse watery diarrhoea. Heat-labile toxin of ETEC acts the same way |
| Whooping cough | Pertussis toxin ADP-ribosylates Gi, disabling it → ↑ cAMP; lymphocytosis, insulin release |
| McCune-Albright syndrome | Activating Gsα mutation in some cells (mosaic): fibrous dysplasia of bone, café-au-lait spots (irregular "coast of Maine" edges), precocious puberty |
| Pseudohypoparathyroidism | Gsα loss (end-organ resistance to PTH): low calcium, high phosphate, high PTH, short stature, short 4th and 5th metacarpals (Albright hereditary osteodystrophy) |
| Nephrogenic diabetes insipidus | V2 receptor or aquaporin-2 defect: kidney does not respond to ADH; also caused by lithium and hypercalcaemia |
| Androgen insensitivity syndrome | Androgen (nuclear) receptor defect: 46,XY with female external appearance, testes present |
| Type 2 diabetes | Post-receptor insulin resistance |
| Laron dwarfism | GH receptor defect: high GH, low IGF-1 |
| Cholera, anthrax (oedema factor) | Increased cAMP (anthrax oedema factor is itself an adenylyl cyclase) |
Expect: group I vs group II hormones, which hormones use nuclear receptors, Gs vs Gi vs Gq with examples, the steps of the cAMP and IP3/DAG pathways, phosphodiesterase and theophylline, cGMP with NO, ANP and sildenafil, insulin's tyrosine kinase receptor, JAK-STAT hormones, cholera and pertussis toxins, McCune-Albright and pseudohypoparathyroidism.
Quick revision
- Nuclear receptors: steroids, T3, calcitriol, retinoic acid (slow, gene transcription).
- Gs → cAMP → PKA: glucagon, PTH, TSH, ACTH, LH, FSH, ADH-V2, β receptors.
- Gq → IP3/Ca²⁺ + DAG/PKC: α1, M1, M3, ADH-V1, oxytocin, GnRH, TRH, angiotensin II.
- Gi ↓ cAMP: α2, M2. PDE breaks cAMP (theophylline blocks).
- cGMP: NO, ANP (sildenafil blocks PDE5).
- Insulin: tyrosine kinase. GH, prolactin, EPO: JAK-STAT.
- Cholera: Gs stuck on. Pertussis: Gi off.
Written by The House Job from standard biochemistry references (Lippincott Illustrated Reviews: Biochemistry).
FAQ
Which hormones act through intracellular receptors?
Steroid hormones, thyroid hormones, calcitriol (active vitamin D) and retinoic acid.
Which second messenger does glucagon use?
Cyclic AMP, through a Gs protein and adenylyl cyclase.
How does cholera toxin cause diarrhoea?
It permanently activates the Gs protein in intestinal cells, raising cAMP, which drives chloride and water secretion into the gut.
What type of receptor does insulin act on?
A receptor tyrosine kinase.