Action Potentials (L6-12)

Action Potentials (L6-12)

1. Resting Membrane Potential

   • Nernst Equation for equilibrium potential
     • Ek = -90mV
       • Means you need to apply -90mV to the cell to keep K from following concentration gradient out
     • ENa = +60mV
     • ECl = -70mV
   • Goldman Equation for RMP combines all EP
     • Typically -70mV
       • So K diffuses out, Na diffuses in, no net Cl diffusion

2. Action Potential

   • @ threshold -55mV
     • Na+ voltage gated channel opens, depolarizing membrane to +45mV
       • K+ voltage gated channel opens (0.5ms delay), repolarizing membrane to -70mV
         • Hyperpolarizes below -70 as it reequilibriates
       • positive feedback loop
       • Inactivation gate closes, enters refractory period
       • Tetrodoxin blocks Na+ VG channel
         • Reaches threshold but no depolarization
       • Greyanotoxin blocks Na+ inactivation gate
         • Resists repolarization
       • Tetraethylammonium (TEA) & Dendrotoxin inhibits K+ VG channel preventing repolarization
       • Local anaesthetics act on the Na+ activation gate
     • Cell maintains homeostasis up to -55mV
       • Na/K pump
       • K leaks out of cell
       • Cl leaks into cell
       • Depolarizing subthreshold = EPSP
         • Hyperpolarizing subthreshold = IPSP
   • Neurons 1-2ms, Heart 300ms

3. AP Propagation

   • Local + charge inside axon is attracted to proximal - charge
     • Initially can move any direction but once directionality is established refractory period keeps it moving forward
   • Myelin prevents ion leakage, speeding up AP
     • AP channels at Nodes of Ranvier
       • Thicker axons = faster AP propagation
     • MS demyelinates axons

4. Skeletal Muscle

   • Neuromuscular Junction
     • AP in alpha-motor neuron
       • Depolarization of neuron terminal
         • Voltage-gated Ca channels open, Ca enters terminal
           • Acetylcholine (Ach) vesicles in terminal fuse to membrane, releasing Ach
             • Ach diffuses to muscle folded endplates
               • 2 Ach bind to Ach-Nicotinic (n1) receptors, opening channel for K and Na to pass through
                 • Muscle membrane depolarizes, opening VG channels
                   • AP propagates through muscle from endplate
                     • Acetylcholinesterase breaks down Ach, closing channels
                     • AP spreads over sarcolemma and down T-tubules
                       • DHP receptor on T-tubule changes conformation
                         • Ryanodine receptor/Ca release channel on SR opens, Ca diffuses to thin filaments (fast)
                           • Ca binds to troponin C, pulls tropomyosin off actin's myosin binding sites and myosin binds to actin forming crossbridges
                             • Myosin head power stroke
                               • Sarcomere shortens
                                 • Ca pumped back into SR by Ca-ATPase (slow)
                                   • Tropomyosin covers Actin's myosin sites again
                                     • Muscle relaxes (slow)
                               • Actin
                                 • Actin
                                   • Actin + Myosin + ADP + Pi
                               • Myosin + ATP
                                 • Myosin + ADP + Pi
                                   • Actin + Myosin + ADP + Pi
                                     • Actin + Myosin
                                 • 1. ATP Hydrolyzed. Rate limiting step
                                   • 2. AP on muscle cell releases Ca to expose myosin binding site on Actin
                                     • 3. Crossbridge formation. Pi ejected, triggering power stroke. ADP released after power stroke
                                       • 4. Crossbridge remains until new ATP binds to Myosin, releasing actin
                                         • Continues until ATP runs out (Rigor mortis) or Ca is gone (pumped back into SR)
     • 1 AP in neuron = 1 AP in muscle
     • Botulin blocks release of Ach, leads to muscular paralysis
     • Nerve gas blocks acetylcholinesterase, keeping channels open and muscles contracted
     • Myasthenia Gravis autoimmune disease that blocks Ach receptors. Treated with Neostigmine - competes with antibodies for Ach binding sites
   • Fascicles --> Muscle cells --> Myofibrils --> Myofilaments - thin and thick
     • Membrane = Sarcolemma
       • T-tubules = sarcolemma inside the muscle
         • Sarcoplasmic Reticulum (SR) between, Ca reservoir
     • Thick filaments
       • Myosin
         • 2 long chains forming tail, arm, hinge, and 1 head
         • Head contains 2 light protein chains - binding ATP and Actin
       • Titin
         • Holds thick filaments in place, prevents overstretching
       • M-line
         • Down middle of thick filaments, holding them in place
     • Thin filaments
       • G-Actin
         • 2 alpha-helices, myosin binding site
       • Tropomyosin
         • alpha helix that covers myosin binding sites
       • Troponin
         • Holds tropomyosin over myosin binding site. Has a Ca binding site that releases the tropomyosin
       • Z-lines
         • Connects thin filaments keeping them in place
         • Sarcomere is distance between Z-lines
   • Motor units
     • 1 alphamotor neuron and all the muscles it innervates
       • each muscle has 1 neuron, but multiple muscles per neuron
         • Small diameter = small # of muscles
     • More motor units = stronger twitch
       • Varying AP frequency can cause multiple twitches that sum without time for the muscle to relax
         • No relax = complete tetanic contraction ~30 Hz
   • Muscle fiber types
     • Type I - slow-oxidative
       • Marathoners
         • Low myosin ATPase. 100ms contraction
           • High myoglobin (dark)
             • Small motoneurons
               • Recruited first
     • Type IIa - fast-oxidative
     • Type IIb - fast-glycolytic
       • Sprinters
         • High myosin ATPase. 10ms contraction
           • Glycolysis - easily fatigued
             • Low myoglobin (light)
               • Large motoneurons
                 • Recruited last

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