Chemical Synaptic Transmission 2

• G protein-coupled receptors (GPCRs)


  Receptors that signal through G proteins
• Receptor superfamilies


  • Ligand-gated ion channels (ionotropic)
  • Kinase-linked receptors (e.g. insulin receptor)
  • Nuclear receptors (e.g. steroid receptors)
  • G protein-coupled receptors (metabotropic)
• G protein-coupled receptors


  • Have a 7 transmembrane domain structure
  • The N-terminus is extracellular and the C-terminus intracellular
  • G proteins interact with the intracellular loops connecting TM domains 3 and 4, 5 and 6, and the C-terminus
• GPCR families


  • Class A - Rhodopsin family (largest group, amine transmitters, peptides, purines, cannabinoids)
  • Class B - Secretin/Glucagon family
  • Class C - Metabotropic Glutamate/Ca2+-sensor family
• Ligand binding domain (LBD)


  • For Class A GPCRs, the binding site is formed by the TM helices or the extracellular loops
  • For Class B GPCRs, the N-terminus incorporates the LBD
  • For Class C GPCRs, the LBD is in the long N-terminus ("Venus Fly Trap" domain)
• G proteins


  • Heterotrimeric proteins composed of α, β and γ subunits
  • Activated by the binding of guanosine triphosphate (GTP) to the α subunit
• Mechanism of G protein action

  1. Prior to ligand binding, the G protein is in an inactive state with GDP bound

  2. Agonist-induced GPCR activation leads to binding of the G protein trimer and displacement of GDP by GTP on the α subunit, resulting in G protein activation

  3. In the active form, the G protein splits into α and βγ subunits, both of which can activate (or inhibit) effector proteins

  4. The α subunit has GTPase activity, which removes a phosphate group from GTP, forming GDP. Once this has occurred, the G protein reverts to an inactive form and the α and βγ subunits reform as a trimer
• Muscarinic acetylcholine receptor subtypes

  • M1
  • M3
  • M5
  • M2
  • M4
• M1 receptors


  Neural (slow EPSP in ganglia)
• M3 receptors


  Glandular secretion, contraction of visceral smooth muscle, vascular relaxation
• ACh binding to muscarinic M2 receptors


  Promotes the opening of potassium channels through the direct action of G protein βγ subunits
• Potassium channel opening


  Elicits hyperpolarisation of the cardiac muscle membrane potential
• M2 receptor activation


  Decreases the force of atrial contraction through G protein βγ inhibition of voltage-gated calcium channels
• Smooth muscle contraction in guinea-pig ileum

  1. M3 receptor activation stimulates phospholipase Cβ, generating IP3 and DAG as second messengers

  2. IP3 releases Ca2+ from the sarcoplasmic reticulum

  3. Ca2+-calmodulin activates myosin light chain kinase, leading to contraction
• Different GPCRs stimulating the same signal transduction pathway

  Can have convergent actions on the same signalling pathway in the same cell (signal amplification)
• 1. HT binding to 5-HT1A receptors


  Promotes the opening of potassium channels through the direct action of G protein βγ subunits
• Synaptic activation of 5-HT1A receptors

  Causes an IPSP/IPSC that reverses at approximately -100mV (EK+)
• Muscarinic AChR-mediated EPSPs


  Involve the closure of K+ channels
• Muscarinic ACh receptors are involved in excitatory transmission in the hippocampus, a learning centre in the brain
• Intracellular recordings from neurons in the hippocampus show a component of their synaptic responses that is cholinergic
• The synaptic potential is prolonged by the anticholinesterase inhibitor physostigmine, and blocked by the muscarinic antagonist atropine
• Learning objectives


  • Describe the structural and functional aspects of G protein-coupled receptors
  • Understand the diversity of G protein-coupled receptor signalling pathways
  • Explain G protein-coupled receptor modulation of cardiac and smooth muscle
  • Explain the role of G protein-coupled receptors in slow synaptic transmission
  • Understand post-synaptic permeability changes and the generation of slow postsynaptic potentials