Receptor mechanisms

• Receptor mechanisms


  Mechanisms by which the four receptor types act to produce an effect
• Agonists


  Bind to same site as ligand, producing same kind of signal, or bind to another site on receptor, producing no signal themselves but enhancing the signal of endogenous ligand (allosteric)
• Antagonists


  Bind to same site as ligand, diminishing or blocking the signal competitively, or bind to an allosteric site on the receptor, diminishing signal produced by endogenous ligand, or cross the membrane & intercept the signal downstream of the receptor
• Receptor proteins


  • Belong to one of 4 types that differ structurally & functionally
  • 3 of these receptor groups are situated in the cell (plasma) membrane; the fourth is intracellular (cytosol/nucleus)
  • All include a ligand-binding domain & an effector domain

  
• Ion channels

  1. 5 subunits, ligand-gated, conduct Na+, K+, Cl- or Ca2+, alter cell membrane potential or intracellular ionic composition, fast communication (s-ms)
• nAChR


  • Na+ permeable, 0.65 nm pore, cation selective
• G protein-coupled receptors


  Receptors linked to effectors (adenylate cyclase/phospholipase C/ion channels) that change intracellular level of second messenger(s), via GTP-binding proteins (G proteins)

  
• GPCR general mechanism


  1. Ligand binds receptor

  2. GDP-GTP exchange on G protein

  3. Effector enzyme or ion channel activated

  4. Second messenger(s) generated

  5. Intracellular effects

  
• 1. protein coupled receptors


  • Single polypeptide chain (800-1,100 aa residues), spanning membrane 7 times
  • Third intracellular loop couples to G protein & determines G-protein selectivity
  • Smaller ligands bind within helix cluster, larger ligands at extracellular surface
• 1. protein coupled receptors


  • Muscarinic acetylcholine receptor (mAChR)
  • GABAB receptor
  • 5-HT (serotonin) receptors (except 5-HT3)
  • Adrenoceptors
  • Histamine H2, eicosanoid, many peptide & purine receptors
  • Dopamine receptors
  • Opioid receptors
  • Chemoreceptors
• Protease activated receptors

  Receptor activated by protease cleavage of N-terminus domain, revealing a 'tethered agonist'
• G proteins


  • Subtypes either activate (Gs, Gq) or inhibit (Gi, G0) specific effectors
  • Signalling takes seconds to minutes
  • Scope for signal amplification
  • Second messengers generated in turn activate protein kinases that phosphorylate target proteins

  
• Second messengers


  cAMP, cGMP, diacylglycerol, IP3, Ca2+
• Receptors with direct kinase activity

  Receptors for polypeptide hormones regulating cell proliferation & differentiation, comprising an extracellular ligand-binding domain, a single membrane-spanning domain, and an intracellular catalytic kinase domain

  
• Receptors with direct kinase activity

  • Epidermal growth factor (EGF) receptor
  • Insulin-like growth factor (IGF-1) receptor
  • Nerve growth factor (NGF) receptor
  • Platelet-derived growth factor (PDGF) receptor

  
• Tyrosine kinase receptors


  Regulate growth, differentiation, development
• Serine/threonine kinase receptors


  e.g. Tumour growth factor (TGF) β receptor
• Receptor tyrosine kinase (RTK) signalling

  1. Ligand binding

  2. Receptor dimerization & autophosphorylation

  3. Activation of Ras/Raf/MEK/MAP kinase pathway

  4. Altered gene transcription
• Cytokines


  Soluble proteins that regulate cell growth, differentiation & function
• Cytokine receptor signalling


  Ligand binding activates Jak kinases, which phosphorylate and activate Stat transcription factors, leading to altered gene transcription

  
• Intracellular receptors


  • Mediate cell response to lipid-soluble ligands like steroids, thyroid hormone, and xenobiotic inducers of drug metabolism
  • Process takes minutes to hours
  • Therapeutic consequences include lag in response and persistent effects
• Intracellular receptors

  • Comprise a ligand-binding domain, a DNA-binding domain, and a transcription-activating domain
  • Ligand binding causes receptor to dissociate from chaperone proteins and translocate to the nucleus, where it binds to response elements in DNA and alters transcription of specific genes

  
• PPARs

  Peroxisome proliferator-activated receptors that bind fatty acids and metabolites, regulating genes for lipid/carbohydrate metabolism and transport
• PPAR subtypes


  • PPARα, PPARγ1/2, PPARδ
• Cell response to ligand or drug is via any of 4 general signalling pathways that integrate extracellular chemical (& physical) information
• Receptors are located in the cell membrane or intracellularly

  
• Signalling rate ranges from rapid (ligand-gated ion channels) to slow (intracellular receptors)
• Specificity of signalling depends on target enzymes/ion channels expressed in a particular cell type, resulting in appropriate response

  
• Receptor number & activity may vary over time
• What are the 4 protein receptor classes?


  Ionotropic, Metabotropic, Enzyme-linked, Intracellular
• Ion channels

  • 4-5 subunits
  • ligand-gated
  • Conduct Na+, K+, Cl-, or Ca2+
• Examples of ion channels

  • Nicotinic acetylcholine receptor (nAChR)
  • GABAa receptor
  • Glyine receptor
  • Glutamate receptors
  • 5-HT3 receptor
  • P2x purine receptor
• G protein-coupled receptors are receptors linked to effectors that change the intracellular level of second messengers via GTP-binding proteins(G-proteins)