Ligands and Receptors Overview

Ligands & Receptors

• Ligands are molecules that bind to receptors.
• Ligands can be endogenous (e.g. neurotransmitters, hormones, inflammatory mediators) or exogenous (e.g. drugs).
• Ligand binding to a receptor alters the receptor's conformation, triggering a cellular response.

Receptor Families

• Four main receptor families:
  • Ligand-gated ion channel receptors (ionotropic receptors)
  • G-protein-coupled receptors (GPCRs)
  • Receptor tyrosine kinases (RTKs)
  • Intracellular receptors

Ligand-gated Ion Channel Receptors

• Activated by binding of endogenous ligands.
• Allow ion passage through the impermeable cell membrane.
• Ion conductivity is highly selective (e.g. GABA receptors for Cl- ions, Glutamate receptors for Na+ and K+ ions).
• Multi-protein subunit assemblies mediate fast signaling at synapses (fraction of a millisecond).

Example: GABAA Receptors

• GABA is the main inhibitory neurotransmitter.
• GABAA receptors are ligand-gated ion channel receptors.
• Pentameric structure formed from two α, two β, and one γ subunit, with multiple subunit isoforms.
• Receptor properties vary depending on subunit combination.
• GABA binding site formed by peptide loops between an α and β subunit.
• Therapeutic use:
  • Main drug target for benzodiazepines (e.g. diazepam, lorazepam, clobazam).
  • Benzodiazepine binding site is formed between the α and γ subunit.
  • Applications: sedation, anxiolytic, epilepsy treatment.

G-protein-coupled Receptors (GPCRs)

• Monomeric proteins with 7 transmembrane domains.
• Coupled to G-proteins:
  • Gi: inhibits adenylate cyclase
  • Gs: stimulates adenylate cyclase
  • Gq: activates phospholipase C
• Mediates activation of downstream signaling cascades leading to a cellular response.

Example: Muscarinic Receptors

• Five muscarinic receptor subtypes: M1, M2, M3, M4, and M5.
• All activated by acetylcholine (non-selective).
• Differences in primary structure, tissue distribution, pharmacological properties, and signal transduction activity.

Other Drugs Acting through GPCRs

• β-adrenoceptors: isoprenaline
• Adenosine receptors: caffeine, theophylline
• Dopamine receptors: L-dopa, haloperidol
• Opioid receptors: morphine, codeine
• Serotonin receptors: buspirone, ondansetron
• Cannabinoid receptors: cannabis, rimonabant, Sativex

Receptor Tyrosine Kinases (RTKs)

• Extracellular ligand binding domain and intracellular kinase enzyme domain.
• Transfer phosphate groups from ATP to tyrosine residues on target proteins (phosphorylation).
• Phosphorylation controls protein function by:
  • Altering enzyme activity (on/off state)
  • Changing subcellular location
  • Modifying interactions with other proteins (adaptor proteins, kinases, phosphatases, lipases)

Example: Vascular Endothelial Growth Factor Receptors (VEGF Receptors)

• Essential for angiogenesis (blood vessel formation) during development, pregnancy, and wound healing.
• Associated with pathophysiological conditions like heart disease and limb ischemia.

Nuclear/Steroid Hormone Receptors

• Located in the cytosol and nucleus.
• Hormone (ligand) binds to the receptor, forming a dimer that translocates to the nucleus.
• Acts as a transcription factor to stimulate target gene expression.

Receptor Summary

• Ligand-gated ion channels: direct coupling, rapid signaling, ion channel as effector (e.g. nicotinic, GABAa).
• GPCRs: G-protein coupling, mediated by downstream signaling cascade, channel or enzyme as effector (e.g. dopamine, cannabinoid, adenosine, muscarinic).
• Kinase-linked receptors: direct coupling, kinase enzyme as effector (e.g. insulin, growth factors, cytokines).
• Nuclear receptors: hormone-receptor dimer translocates to nucleus, gene transcription as effector (e.g. steroid, thyroid hormone).

Adenosine Receptor Subtypes

• Adenosine receptors can be A1 or A2B.
• Non-selective adenosine agonist CPA can induce bronchial ring contraction.
• Selective A1 antagonist 8-CPT blocks contraction induced by CPA, suggesting A1 receptor involvement.
• Selective A2B antagonist PSB-601 does not prevent CPA-induced contraction, indicating A2B is not the primary mediator.
• A1 receptor agonists have anticonvulsant effects in mouse models of epilepsy.
• Testing an A1 receptor agonist in a clinical trial for refractory epilepsy might be worthwhile, but further investigation is needed.

Ligand Affinity

• Kd value reflects ligand affinity for a receptor.
• Lower Kd value indicates higher affinity.

Explore the fascinating world of ligands and receptors in cellular communication. This quiz covers the types of ligands, receptor families, and the function of ligand-gated ion channels, focusing on examples like GABAA receptors. Test your understanding of these essential biological concepts and their implications in pharmacology and neuroscience.