4.4 Nuclear Receptors
Nuclear receptors are ligand-activated transcription factors that regulate gene expression. They mediate the effects of steroid hormones, thyroid hormone, retinoids, and vitamin D, producing slow-onset but long-lasting physiological changes.
Structure and Mechanism
Domain Structure
- • N-terminal domain (NTD): Activation function-1 (AF-1), ligand-independent transcriptional activation
- • DNA-binding domain (DBD): Two zinc fingers that recognize hormone response elements (HREs)
- • Hinge region: Flexible linker, nuclear localization signals
- • Ligand-binding domain (LBD): Ligand binding pocket + AF-2 (ligand-dependent activation)
- • C-terminal domain: Variable region
Mechanism of Action
General pathway:
1. Lipophilic ligand crosses cell membrane
2. Binds to nuclear receptor (cytoplasm or nucleus)
3. Conformational change releases corepressors, recruits coactivators
4. Receptor dimerization (homo- or heterodimers)
5. Binding to HREs in DNA (promoter/enhancer regions)
6. Recruitment of transcriptional machinery
7. Altered gene transcription → new protein synthesis (hours to days)
Classification
Type I: Steroid Receptors
Cytoplasmic when unbound, translocate to nucleus upon ligand binding. Homodimerize.
- • Glucocorticoid receptor (GR)
- • Mineralocorticoid receptor (MR)
- • Androgen receptor (AR)
- • Estrogen receptor (ER α/β)
- • Progesterone receptor (PR)
Type II: Non-Steroid Receptors
Constitutively nuclear, bound to DNA as heterodimers with RXR (retinoid X receptor).
- • Thyroid hormone receptor (TR α/β)
- • Vitamin D receptor (VDR)
- • Retinoic acid receptor (RAR α/β/γ)
- • Peroxisome proliferator-activated receptor (PPAR α/γ/δ)
- • Liver X receptor (LXR)
Therapeutic Agents: Steroid Receptors
Glucocorticoid Receptor Agonists
Drugs: Prednisone, dexamethasone, hydrocortisone, budesonide, fluticasone
Mechanism: GR activation → ↑ anti-inflammatory proteins (lipocortin, IL-10), ↓ pro-inflammatory genes (COX-2, iNOS, cytokines)
Uses: Asthma, COPD, rheumatoid arthritis, IBD, organ transplant, allergic reactions
Adverse effects: Immunosuppression, osteoporosis, hyperglycemia, Cushing syndrome, HPA axis suppression
Estrogen Receptor Modulators
Agonists: Estradiol, ethinyl estradiol (contraception, HRT)
SERMs (Selective ER Modulators): Tamoxifen (ER antagonist in breast, agonist in bone/uterus - breast cancer), raloxifene (agonist in bone, antagonist in breast - osteoporosis)
Pure antagonists: Fulvestrant (metastatic breast cancer)
Androgen Receptor Modulators
Agonists: Testosterone, nandrolone (hypogonadism, anemia)
Antagonists: Flutamide, bicalutamide, enzalutamide (prostate cancer)
5α-reductase inhibitors: Finasteride (blocks testosterone → DHT conversion, BPH/male pattern baldness)
Progesterone Receptor Modulators
Agonists: Progesterone, medroxyprogesterone (contraception, HRT, endometriosis)
Antagonist: Mifepristone (RU-486, medical abortion, Cushing syndrome)
Mineralocorticoid Receptor Antagonists
Drugs: Spironolactone, eplerenone
Uses: Hypertension, heart failure, primary hyperaldosteronism; spironolactone also used in hirsutism/acne (anti-androgen effects)
Therapeutic Agents: Non-Steroid Receptors
Thyroid Hormone Receptor Agonists
Levothyroxine (T4), liothyronine (T3): Hypothyroidism replacement
Mechanism: TR-RXR heterodimer → gene transcription affecting metabolism, development, cardiovascular function
Vitamin D Receptor Agonists
Calcitriol (1,25-dihydroxy vitamin D3), paricalcitol: Vitamin D deficiency, secondary hyperparathyroidism, psoriasis
Mechanism: VDR-RXR → ↑ intestinal Ca²⁺ absorption, bone mineralization, immune modulation
Retinoid Receptor Agonists
All-trans retinoic acid (ATRA): Acute promyelocytic leukemia (APL) - induces differentiation
Isotretinoin, tretinoin: Severe acne, photoaging
Teratogenicity: Absolute contraindication in pregnancy
PPAR Agonists
PPARγ agonists: Thiazolidinediones (pioglitazone) - type 2 diabetes, ↑ insulin sensitivity
PPARα agonists: Fibrates (fenofibrate, gemfibrozil) - hypertriglyceridemia, ↑ fatty acid oxidation
Dual PPARα/γ: Investigational for metabolic syndrome
Pharmacological Considerations
Slow Onset/Offset
Effects delayed (hours to days) due to requirement for gene transcription and protein synthesis. Long duration of action.
Tissue Selectivity
SERMs/SARMs exhibit tissue-specific agonist/antagonist activity based on coregulator expression and receptor conformation
Genomic vs Non-Genomic
Classical genomic effects (hours-days). Some steroids also have rapid non-genomic effects (seconds-minutes) via membrane receptors
Drug Resistance
Cancer cells develop resistance via receptor mutations, altered coregulator expression, or activation of alternative pathways