Lecture 8: Voltage- Gated ion channels Gating of ion channels 1. Ligand- Ligand channels = ionotropic receptors - Open or close in response to the binding of a chemical messenger (ligand) - 'Neurotransmitter-gated' - Depolarising > excitatory 2. Metabotropic receptors (G-protein coupled receptors) - Do not form an ion channel pore - Use signal transduction mechanism to activate intracellular events - Themselves do not depolarise or hyperpolarise a cell 3. Mechanically-gated ion channels -> Stretch-gated ion channels - Sense and respond to mechanical stimuli (e.g. touch) - Found in skin, inner ear 4. Voltage-gated ion channels - Open or close in response to the voltage across the membrane o Change in voltage across the membrane - lon specific transmembrane proteins found in all excitable cells -> neurones, muscles etc ... - Closed at the resting membrane potential Voltage-Dependent Na + Required for action potentials Voltage-Dependent K + Required for action potentials Slow activating and fast activating Very diverse Voltage-Dependent Ca2+ Transduce of membrane potential changes into intracellular Ca2+ transients that initiate physiological events Primary Structure of VG Na + and K+ Channel Four domains with 6 transmembrane segments each 1 EXTRACELLULAR 20 IV O - Pore and activation gate: TM 5-6 - Voltage sensors: TM 1-4 - Inactivation gate: Linker loop between III and IV - Beta subunits have a modulatory role 12345 16 12345 INTRACELLULAR 2 pore loop NH 12345 6 12345 U Inactivation gate COOH direction of action potential propagation Propagation of action potentials +40 mV 0 mV -50 mV Site A: Opening of voltage-gated Na+ channels open and the membrane depolarises axon Z A B - ++++ -- ++ +- + K* Na efflux influx
Site B: In 'pre-depolarisaiton' phase -> about to be depolarised Site Z: Refractory period (VG Na+ channels inactivated and VG K+ channels activated) > Prevents retrograde AP propagation Patch Clamp electrophysiology - Enables measurements of electrical current or voltage created as a result of ionic flow through membrane 50 0 50 -100 Na+ channel Functional States of Na+ and K+ voltage-gated channels - K+ channel open with a delay relative to Na+ channels - Depolarisaiton inactivates the Na+ channel but no the K+ Channel - Both activation and inactivation gates must be open for the conduction to occur Closed K+ channel Pathologies associated with Na+ and K+ voltage-gated channels Sodium Channels Closed Na+ Open Closed 5 10 15 Time (ms) . Na+ . Inactivating Inactivated Closed O K+ 00 Open O O K. O O Open Closed - Hyperexcitability (repetitive APs) and impaired muscle relaxation - Both gain-of-function and loss-of-function mutations can lead to paralysis - Mutations in sodium channels associated with seizure disorders including generalized epilepsy o Where epilepsy is the non- regulated overactivation of postsynaptic cells Potassium Channels - Prolonged action potentials and increased cell excitability - In the CNS: generalized epilepsy and dyskinesia (a movement disorder)