Describe how the mechanisms of action potential conduction were discovered.

Sanjay Manohar, Cambridge 2001


Bernstein 1902 - non-specific depolarisation to 0V


1. Cole & Curtis 1939

       Wheatstone bridge during AP

              Membrane Capacitance same, Resistance fell

       => increased membrane permeability


2. Cole & Curtis 1941

       Intracellular recording of AP

              Depolarisation crosses zero

              -55 to +50 mV

3. Hodgkin & Katz 1949 (Sodium hypothesis)

       Replace extracellular Na with glucose

              Reduced AP amplitude & rate of rise

4. Keynes & Lewis 1951

       Radiolabelled 24-Na

              Entry during AP, not while resting

=> Na implicated



5. Hodgkin 1951(Theory)

       Positive feedback proposed

       Halted by 1) E > ENa, 2) inactivation


6. Hodgkin & Huxley 1952

       Voltage clamping: measure current required to hold

       membrane voltage at fixed value.

       a.    Total current vs. voltage

                     biphasic: inwards then outwards

       b.    Replace extracellular Na with choline.

              Current vs. voltage

                     both components outwards

                            => early component is Na


       c.    Repeat with E = ENa, so that INa = 0

              i.e.  if clamping at voltage V, set extracellular [Na]

                     such that ENa = V (using Nernst)

              Current vs. voltage

                     isolated K and Na currents found



              Calculate g = ion current / total potential driving ion

              Conductance vs. voltage


              fit g(V, t) to first order processes (in time) whose

              parameters depend only upon V. n, m, h


              Test this by prediction by modelling AP:

              at any instant, voltage change can be calculated

              voltage change = total current / capacitance

              ion current = conductance x potential driving ion




12. Keynes et al

       Cs+ blocking K current

       TTX blocking Na current

              => confirm H&H current components

       Measurement of gating current.

       Site directed mutagenesis