Drug Targets: Receptors

Receptor Superfamilies

  • Four main types:

    • Ion channel-linked (ionotropic) receptors

    • G-protein-coupled receptors (GPCRs)

    • Kinase-linked receptors

    • Nuclear receptors

1. Ionotropic Receptors

  • Ligand-gated ion channels linked directly to ion channel.

  • Fast neurotransmitters (e.g., nAchR, GABAA receptor, glutamate receptor).

  • Effect: Depolarization/hyperpolarization.

  • Time scale: Milliseconds.

  • Example: Neuromuscular blocking drugs (Pancuronium, vecuronium) block nicotinic acetylcholine receptors.

  • Benzodiazepines modulate GABAA receptors, enhancing GABA effects.

2. G-Protein Coupled Receptors (GPCRs)

  • Coupled via G-proteins to cellular effectors (enzymes or ion channels).

  • Activation of enzymes leads to second messengers.

  • Structure: Single polypeptide chain with 7 transmembrane segments.

  • Families: Rhodopsin, Secretin/glucagon, Metabotropic glutamate receptors.

  • G-protein subtypes: Gαs (stimulates adenylyl cyclase), Gαi (inhibits adenylyl cyclase), Gαq (stimulates phospholipase C).

  • Examples:

    • β adrenoceptors (coupled to Gαs): β1 agonists (adrenaline, dobutamine) for cardiac arrest/shock; β2 agonists (salbutamol) for bronchodilation.

    • Opioid receptors (coupled to Gαi): Morphine as a μ-opioid receptor agonist for pain relief.

    • Muscarinic M3 receptors couple to phospholipase C, leading to smooth muscle contraction.

  • Advances:

    • Dimerization: GPCRs may form homo- and heterodimers.

    • Biased agonism: Ligands can selectively activate different signaling pathways.

3. Kinase-Linked Receptors

  • Membrane receptors linked to kinase activity (tyrosine kinase).

  • Mediate actions of growth factors, cytokines, hormones (e.g., insulin, leptin).

  • Role: Cell division, growth, differentiation, inflammation, tissue repair, apoptosis, immune responses.

  • Mechanism: Ligand binding causes receptor dimerization and autophosphorylation, activating intracellular proteins.

  • Therapeutic example: Insulin for diabetes, Imatinib for chronic myeloid leukemia.

4. Nuclear Receptors

  • Intracellular receptors that modulate gene transcription.

  • Located in nucleus or cytoplasm.

  • Ligand-receptor complex binds to hormone response elements in genes.

  • Two classes:

    • Class I (hormones): Form homodimers, e.g., GR, ER.

    • Class II (lipids): Form heterodimers with RXR, e.g., PPAR, RXR.

  • Therapeutic example: Tamoxifen (oestrogen receptor antagonist) for breast cancer, Glucocorticoids (activate glucocorticoid receptor) for anti-inflammatory effects.