Ion channels, receptors and intracellular signalling

• Ion channels are protein complexes that span the entire cell membrane
• Ion channels

  Allow charged ions (Na+, Ca2+, K+) to pass through the cell membrane
• Ion channels

  • Rate of ion conductance through the cell
  • Direction of conductance
• Ion channel classification

  • Voltage sensitive
  • Ligand dependent
• Many drugs target ion channels and change their status (either open or closed)
• Cation channels

  Allow Na+, K+ or Ca2+ to pass through
• Anion channels

  Allow anions to pass through
• Voltage-sensitive ion channels

  Open in response to membrane potential
• Ligand-dependent ion channels

  Open status changes in response to the binding of a ligand to its receptor site
• Resting potential

  1. When no nerve impulse is being transported along axon, resting potential (-70 mV) is maintained across axon membrane

  2. Stimulus causes Na+ channels to open and Na+ diffuses rapidly into axon down an electrochemical gradient

  3. When threshold is exceeded, causes depolarisation of axon

  4. Action potential is triggered and voltage-sensitive gates of Na+ close and K+ channels open

  5. K+ ions leave the axon down their concentration gradient, causing repolarisation of axon

  6. Slight overshoot of the K+ ions diffusing out results in hyperpolarisation

  7. Sodium-potassium pump restores original Na+ and K+ concentrations, returning to resting potential
• Sodium-potassium pump

  Transports 3 Na+ out and 2 K+ in per ATP, restoring resting potential
• Voltage-gated ion channels

  Membrane potential dependent on inter/extracellular ion concentrations
• Voltage-gated ion channels have a 6-helix (S1-6) structure
• Ion channel structure

  α-subunit forms the channel pore, with 4 transmembrane domains
• Drugs target ion channels by binding to specific sites on the channel structure
• Receptors

  Macromolecular components of the cell that drugs bind to in order to exert their effects
• Receptor agonist

  Binds to a specific receptor and activates it, causing a cellular response
• Receptor antagonist

  Binds to a specific receptor but does not activate it, preventing binding of agonist
• Ligand binding to receptor

  • Rapidly reversible due to weak interactions (H-bonds, ionic bonds, Van der Waals forces)
  • Can be irreversible if interaction is mediated by covalent bonds
• Synaptic transmission

  1. Arrival of electrical stimulus triggers release of neurotransmitter (acetylcholine) into synaptic cleft

  2. Neurotransmitter binds to receptors on postsynaptic membrane, allowing Na+ influx and depolarisation

  3. Neurotransmitter is hydrolysed by enzymes and reabsorbed for recycling
• Electrical synapse

  Action potential triggers release of neurotransmitter, which binds to receptors and causes fast response
• Chemical synapse

  Action potential triggers release of neurotransmitter, which binds to G-protein coupled receptors and causes slow response
• Drug A binds to receptor

  Activates G-protein system to stimulate or inhibit effector system (adenylate cyclase)
• Drug binds to receptor...

  and activates G protein system to stimulate or inhibit effector system (adenylate cyclase)
• If adenylate cyclase is stimulated

  Effector system produces second messenger cAMP
• If adenylate cyclase is inhibited

  cAMP levels decrease
• Active PKA

  Phosphorylates proteins
• Intracellular receptors are DNA-linked nuclear receptors that regulate gene transcription