Nuclear Receptors

Nuclear Receptors: Ligand-Regulated Transcription Factors:

Nuclear receptors (NRs) are intracellular ligand-activated transcription factors.

• They regulate gene expression in response to lipophilic signalling molecules such as:

  • Steroid hormones (e.g., oestrogens, glucocorticoids)

  • Thyroid hormones

  • Retinoids and vitamin D metabolites

• They are essential regulators of development, metabolism, reproduction, and homeostasis.

Cellular Localisation:

• In contrast to membrane-bound receptors (e.g., ion channels and G protein-coupled receptors), nuclear receptors are located within the cytoplasm or nucleus.

  • Their ligands are hydrophobic, enabling passive diffusion through the plasma membrane.

General Mechanism of Action:

• Ligand Entry:

  • Lipophilic ligand diffuses across the plasma membrane.

• Ligand Binding:

  • Ligand binds to its cognate nuclear receptor, inducing a conformational change.

• Dimerisation:

  • The receptor forms a homodimer or heterodimer, enhancing DNA-binding affinity.

• Nuclear Translocation:

  • The receptor–ligand complex translocates to the nucleus if initially cytoplasmic.

• DNA Binding:

  • The complex binds to specific DNA sequences termed Hormone Response Elements (HREs) within the promoter region of target genes.
    

• Transcriptional Regulation:

  • Coactivator proteins (e.g., SRC-1, CBP/p300) promote transcription.

  • Corepressor proteins (e.g., NCoR, SMRT) inhibit transcription.

    • The resultant outcome (gene activation or repression) depends on the cellular context and cofactor availability.

Structural Organisation of Nuclear Receptors:

Each receptor is a single polypeptide chain comprising several conserved domains:

The Oestrogen Receptor (ER):

Ligand and Subtypes:

• Primary ligand: 17β-oestradiol (E2).

• Receptor subtypes:

  • ERα: Predominantly expressed in reproductive tissues (e.g., uterus, breast).

  • ERβ: Found in bone, brain, and cardiovascular tissues.

• Subtype expression contributes to tissue-specific pharmacological responses.

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Mechanism of Action:

• Oestradiol diffuses through the plasma membrane due to its lipophilic nature.

  • It binds to the oestrogen receptor in the cytoplasm or nucleus.

    • Ligand binding induces receptor dimerisation.

      • The receptor–ligand complex binds to Oestrogen Response Elements (EREs) within target gene promoters.

        • Recruitment of coactivators stimulates transcription of oestrogen-responsive genes, while corepressors suppress transcription.

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Physiological Roles of Oestrogen:

• Regulation of female secondary sexual characteristics (e.g., breast development, fat distribution).

• Maintenance of the menstrual cycle and fertility.

• Promotion of bone growth and maintenance.

• In males, contributes to spermatogenesis and sperm maturation.

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Clinical Relevance:

• Many breast cancers are oestrogen receptor-positive (ER⁺) and depend on oestrogen signalling for proliferation.

  • Selective Oestrogen Receptor Modulators (SERMs) (e.g., tamoxifen) exhibit tissue-specific agonist/antagonist activity:

    • Antagonist in breast tissue → inhibits tumour growth.

    • Agonist in bone → preserves bone mineral density.

• The tissue specificity arises from differing patterns of coactivator and corepressor expression in various cell types.

The Glucocorticoid Receptor (GR):

Ligands and Function:

• Endogenous ligand: Cortisol.

  • Synthetic analogues: Dexamethasone, beclomethasone, prednisolone.

    • Primary functions:

      • Regulation of metabolic homeostasis.

      • Mediation of anti-inflammatory and immunosuppressive effects.

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Mechanism of Action:

• Glucocorticoid diffuses across the plasma membrane.

  • Binds to cytoplasmic GR complexed with heat shock proteins (HSP90, HSP70).

    • Ligand binding displaces HSPs and induces receptor dimerisation.

      • The activated receptor translocates into the nucleus.

        • GR binds to specific Glucocorticoid Response Elements (GREs) in DNA.
          

• Regulates transcription through:

  • Transactivation: Upregulation of anti-inflammatory genes (e.g., Annexin-1, IL-10).

  • Transrepression: Inhibition of pro-inflammatory genes (e.g., IL-1β, TNF-α, COX-2).

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Physiological and Pharmacological Effects:

• Anti-inflammatory and immunosuppressive:

  • Inhibit cytokine and chemokine production.

  • Decrease vascular permeability.

  • Suppress leukocyte migration.

• Clinical applications:

  • Treatment of asthma, rheumatoid arthritis, dermatitis, inflammatory bowel disease, and allergic reactions.

• Adverse effects (with chronic use):

  • Hypertension, mood alterations, hyperglycaemia, weight gain, and osteoporosis.