Nuclear Receptors - Pharmacology 3A Notes

Block 1: Principles of Pharmacology - Nuclear Receptors

Intended Learning Outcomes (ILOs)

• Understand the concept of nuclear receptors.
• Describe the activation process of nuclear receptors and the resulting effects.
• Identify drugs targeting nuclear receptors and their therapeutic uses.

Key Reference

• Volle D.H. (2016) "Nuclear receptors as pharmacological targets, where are we now?" Cell. Mol. Life Sci. 73: 3777-3780. PubMed Link
• Additional Reference: PubMed Link

History of Nuclear Receptors

• 1905: Term "hormone" coined by Ernest Starling.
• 1926: Cortisone and thyroxine isolated by Edward Calvin Kendall and Tadeus Reichstein.
• 1929: Oestrogen isolated by Adolph Butenandt and Edward Adelbert Doisy.
• 1958: Oestrogen receptor isolated by Elwood Jensen.
• 1970s: Presence of steroid hormone receptors in cytoplasm established; translocation to nucleus upon binding.
• 1980s: Cloning of oestrogen, glucocorticoid, and thyroid hormone receptors.
• 2004: Albert Lasker Award for Basic Medical Research awarded to Pierre Chambon, Ronald Evans, and Elwood Jensen.

Nuclear Receptors: Key Points

• Located within cells, they influence physiological events over long periods.
• Ligands include steroid and thyroid hormones.
• Once activated, they work with proteins to regulate gene expression, affecting development, growth, homeostasis, and metabolism.
• They bind directly to DNA, regulating nearby genes.
• Activation requires ligand binding, resulting in conformational changes and subsequent gene regulation.

Nuclear Receptors: Structure

• Molecular Weight: 50,000 - 100,000 daltons.
  • (A-B) N-terminal regulatory domain: highly variable.
  • (C) DNA-binding domain (DBD): conserved; binds DNA through hormone response elements (HRE).
  • (D) Hinge region: flexible; connects DBD and LBD, influences distribution.
  • (E) Ligand-binding domain (LBD): moderately conserved; binds coactivators/repressors.
  • (F) C-terminal domain: variable across different receptors.

Types of Nuclear Receptors

• Type I (Class I): Steroid hormone receptors (e.g., glucocorticoid, mineralocorticoid, estrogen, progesterone, androgen).

  • Predominantly located in the cytoplasm, bound to heat shock proteins (HSP).
  • Ligand binding forms homodimers that translocate to the nucleus, regulating gene expression.

• Type II (Class II): Receptors for ligands already within cells (e.g., PPAR, LXR, FXR, Vitamin A/D receptors).

  • Typically operate as heterodimers with retinoid receptors (RXR).
  • Induce drug-metabolizing enzymes (e.g., CYP3A).

Nuclear Receptors: Co-Regulatory Proteins

• Once bound to HREs, nuclear receptors recruit transcription co-regulators.
  • Coactivators: Facilitate gene transcription in response to agonists.
  • Corepressors: Inhibit gene transcription in response to antagonists.

Nuclear Receptors: Drug Targets

• PPAR Receptors:
  • Subtypes include PPARα (liver, kidney), PPARβ (brain, skin), and PPARγ (widespread).
  • Functions include cellular differentiation, metabolism regulation, potential roles in diseases (e.g., Type 2 Diabetes).
• PPAR Agonists:
  • E.g., Glitazones (Thiazolidinediones), enhance gene transcription, improve glucose metabolism.

Drug Mechanism of Action (MoA)

• Fibrates: Lower serum triglycerides; effective in specific conditions, used as second-line agents.
• Glucocorticoids: Commonly used in conditions like asthma, Crohn's disease, delivered through various methods (creams, drops).