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Hodgin & Huxley

Hodgin & Huxley. The problem: Explain action potentials The preparation: loligo giant axons What was known: Time dependent conductance: Curtis & Cole Multiple batteries in play Likely players Na + , K + : Hodgkin & Katz A new method: Voltage Clamp. Action Potentials “Overshoot”.

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Hodgin & Huxley

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  1. Hodgin & Huxley • The problem: Explain action potentials • The preparation: loligo giant axons • What was known: • Time dependent conductance: Curtis & Cole • Multiple batteries in play • Likely players Na+, K+ : Hodgkin & Katz • A new method: Voltage Clamp

  2. Action Potentials “Overshoot” Hodgkin & Huxley, 1939 Nature 144:473-96

  3. Loligo forbesi

  4. Parallel conductance model

  5. How to study the process of action potential generation

  6. Voltage Clamp • 3 electrodes used: • Vo • Vi • Ii (injected current, measured with I-mon) • Advantages • Space clamp – axial wires used – • Can effectively eliminate Ic – V is fixed • Used to isolate time dependent changes in I

  7. Voltage clamp currents in loligo Modern convention: • Original presentation: • - Vm relative to rest • -referenced to inside of cell • amplitude & polarity appropriate • for necessary charging of membrane

  8. Isolation of the “outward current”

  9. gK(t) • Sigmoid onset • Noninactivating • Exponential offset

  10. Model of gK

  11. Equilibrium n(V), noo • Similar to a Boltzmann distribution

  12. Rate constants for gate n • Derived from onset or offset of gK upon DV

  13. gK fitted to HH equation • Reasonable fit to onset, offset & steady state

  14. Isolate iNa by algebraic subtraction • Appears Ohmic • Sigmoidal onset • Increase in gNa is reversible • g(V) is independent of i sign

  15. Current flow through pNa is Ohmic • Open channel I/V curve • Instantaneous conductance

  16. gNa kinetics • Both activation and inactivation speed up with depolarization

  17. Model of gNa

  18. hoo • Determined with prepulse experiments

  19. Rate constants for gate h • Derived from onset or offset of gNa upon DV

  20. Rate constants for gate m • Derived from onset or offset of gNa upon DV

  21. Summary of equilibrium states and time constants for HH gates

  22. HH model equations - All as and bs are dependent on voltage but not time - Calculate I from sum of leak, Na, K - Can calculate dV/dt, and approximate V1 =V(t+Dt)

  23. HH fit to expermentally determined gNa

  24. Voltage clamp currents are reproduced by simulations

  25. …as are action potentials

  26. Evolution of channel gates during action potential

  27. Modern view of voltage gated ion channels

  28. Markov model of states & transitions • Allosteric model of Taddese & Bean • Only 2 voltage dependent rates

  29. Allosteric model results • Reproduces transient & sustained current

  30. Generality of model • Many ion channels described in different neuronal systems • Each has unique • Equilibrium V activation range • Equilibrium V inactivation range • Kinetics of activation and inactivation • Reversal potential • These contribute to modification of spike firing in different V and f domains

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