I now have all the key diagrams from Harper's. Here is the complete response with all diagrams:
Mechanisms of Hormone Action - Harper's Illustrated Biochemistry, 32nd Ed.
Harper's classifies hormones into two groups based on their mechanism of action:
FIGURE 42-1: Overall Framework - Group I vs Group II Hormones
Group I hormones (steroids, thyroid hormones, Vitamin D, retinoic acid) - interact with intracellular receptors → form hormone-receptor complex → regulate gene transcription
Group II hormones (peptides, catecholamines) - interact with cell surface membrane receptors → generate second messengers → many different cellular effects
FIGURE 41-2A: Chemical Structure - Cholesterol Derivatives (Steroid Hormones)
Steroid hormones (17β-Estradiol, Testosterone, Cortisol, Progesterone) and 1,25(OH)₂-D₃ are all derived from cholesterol via the steroidogenic pathway.
FIGURE 41-2B: Chemical Structure - Tyrosine Derivatives (Amino Acid-derived Hormones)
T3 and T4 (thyroid hormones) and catecholamines (Norepinephrine, Epinephrine) are all derived from the amino acid Tyrosine. Thyroid hormones additionally require iodination.
FIGURE 42-3: The "Information Pathway" - How Group I Hormones (Steroids) Work
Mechanism of Group I (Steroid/Nuclear) Hormones:
- The lipid-soluble hormone diffuses across the cell membrane
- Binds to intracellular nuclear receptor (NR superfamily)
- The hormone-receptor complex binds to specific Hormone Response Elements (HREs) in DNA
- Regulates transcription of specific genes
- Hormones can act at any step: transcription, mRNA processing, mRNA transport, translation, or protein modification
Key HREs from Harper's:
| Hormone | Response Element | DNA Sequence |
|---|
| Glucocorticoids | GRE | GGTACA NNN TGTCT |
| Estrogens | ERE | AGG TCA - TGACCT |
| Thyroid hormone | TRE | AGG TCA N(1-5) AGG TCA |
| Vitamin D | VDRE | Direct repeats (N=3) |
| cAMP-mediated | CRE | TGACGTCA |
FIGURE 42-4: G-Protein Coupled Receptor (GPCR) Mechanism - Group II Hormones
Mechanism:
- GPCRs have 7 transmembrane alpha-helical domains
- Without hormone (left): G-protein (αβγ) is in inactive GDP-bound form
- Hormone (H) binds receptor → conformational change → G-protein associates with receptor
- GDP exchanges for GTP on the α subunit → α and βγ dissociate
- α subunit activates the effector (E): adenylyl cyclase, phospholipase C, or ion channels
- Generates second messengers: cAMP, IP₃, DAG, Ca²⁺
FIGURE 42-5: cAMP → Protein Kinase A (PKA) Pathway
cAMP Second Messenger Pathway (step by step):
- Hormone binds GPCR → activates Gs protein → activates adenylyl cyclase
- Adenylyl cyclase converts ATP → cAMP (requires Mg²⁺)
- cAMP binds to R₂C₂ inactive PKA → regulatory (R) and catalytic (C) subunits dissociate
- Active C₂ (PKA) phosphorylates target proteins on Ser/Thr residues
- Phosphatase removes the phosphate to terminate the response
- Phosphodiesterase degrades cAMP → 5'-AMP (also terminates signal)
Hormones stimulating adenylyl cyclase (via Gs): ACTH, ADH, β-adrenergics, FSH, glucagon, LH, PTH, TSH, calcitonin, CRH
Hormones inhibiting adenylyl cyclase (via Gi): Acetylcholine, α₂-adrenergics, angiotensin II, somatostatin
FIGURE 42-6: Phosphatidylinositol / Ca²⁺ / PKC Pathway
IP₃ / DAG / Ca²⁺ Second Messenger Pathway:
- Hormone binds receptor → via Gq protein → activates Phospholipase C (PLC)
- PLC cleaves PIP₂ (phosphatidylinositol 4,5-bisphosphate) into:
- IP₃ (inositol trisphosphate) - releases Ca²⁺ from endoplasmic reticulum
- DAG (diacylglycerol) - activates Protein Kinase C (PKC)
- Elevated cytosolic Ca²⁺ binds calmodulin
- Ca²⁺-calmodulin activates specific and multifunctional calmodulin kinases
- Kinases phosphorylate target proteins → Physiologic responses
Hormones using this pathway: Acetylcholine, ADH (vasopressin), α₁-adrenergic catecholamines
Summary Table - Harper's Classification of Hormone Mechanisms
| Feature | Group I (Steroid/Nuclear) | Group II-A (cAMP) | Group II-B (Ca²⁺/IP₃) |
|---|
| Examples | Cortisol, T3/T4, Estrogen, Vit D | ACTH, TSH, FSH, Glucagon | Acetylcholine, ADH, α₁-agonists |
| Receptor location | Intracellular (nucleus/cytoplasm) | Cell surface (GPCR 7-TM) | Cell surface (GPCR 7-TM) |
| 2nd messenger | None (direct gene action) | cAMP → PKA | IP₃ + DAG → Ca²⁺ + PKC |
| Final effect | Gene transcription | Protein phosphorylation | Protein phosphorylation |
| Onset | Slow (hours) | Fast (minutes) | Fast (seconds-minutes) |
Source: Harper's Illustrated Biochemistry, 32nd Ed., Chapter 41 & 42