THE MODERN IONIC HYPOTHESIS

Hodgkin, Huxley, and Katz [(3)] and Hodgkin and Huxley [(14)], [(15)], [(16)], in 1952, published a series of papers describing detailed measurements of voltage, current, and time relationships in the giant axon of the squid (Loligo). Hodgkin and Huxley [(17)] consolidated and formalized these data into a set of simultaneous differential equations describing the hypothetical time course of events during spike generation and propagation. The hypothetical system which these equations describe is the basis of the Modern Ionic Hypothesis.

The system proposed by Hodgkin and Huxley is basically one of dynamic opposition of ionic fluxes across the axon membrane. The membrane itself forms the boundary between two liquid phases—the intracellular fluid and the extracellular fluid. The intracellular fluid is rich in potassium ions and immobile organic anions, while the extracellular fluid contains an abundance of sodium ions and chloride ions. The membrane is slightly permeable to the potassium, sodium, and chloride ions; so these ions tend to diffuse across the membrane. When the axon is inactive (not propagating a spike), the membrane is much more permeable to chloride and potassium ions than it is to sodium ions. In this state, in fact, sodium ions are actively transported from the inside of the membrane to the outside at a rate just sufficient to balance the inward leakage. The relative sodium ion concentrations on both sides of the membrane are thus fixed by the active transport rate, and the net sodium flux across the membrane is effectively zero. The potassium ions, on the other hand, tend to move out of the cell; while chloride ions tend to move into it. The inside of the cell thus becomes negative with respect to the outside. When the potential across the membrane is sufficient to balance the inward diffusion of chloride with an equal outward drift, and the outward diffusion of potassium with an inward drift (and possibly an inward active exchange), equilibrium is established. The equilibrium potential is normally in the range of 60 to 65 millivolts.

The resting neural membrane is thus polarized, with the inside approximately 60 millivolts negative with respect to the outside. Most of the Hodgkin-Huxley data is based on measurements of the transmembrane current in response to an imposed stepwise reduction (depolarization) of membrane potential. By varying the external ion concentrations, Hodgkin and Huxley were able to resolve the transmembrane current into two “active” components, the potassium ion current and the sodium ion current. They found that while the membrane permeabilities to chloride and most other inorganic ions were relatively constant, the permeabilities to both potassium and sodium were strongly dependent on membrane potential. In response to a suddenly applied (step) depolarization, the sodium permeability rises rapidly to a peak and then declines exponentially to a steady value. The potassium permeability, on the other hand, rises with considerable delay to a value which is maintained as long as the membrane remains depolarized. The magnitudes of both the potassium and the sodium permeabilities increase monotonically with increasing depolarization. A small imposed depolarization will result in an immediately increased sodium permeability. The resulting increased influx of sodium ions results in further depolarization; and the process becomes regenerative, producing the all-or-none action potential. At the peak of the action potential, the sodium conductance begins to decline, while the delayed potassium conductance is increasing. Recovery is brought about by an efflux of potassium ions, and both ionic permeabilities fall rapidly as the membrane is repolarized. The potassium permeability, however, falls less rapidly than that of sodium. This is basically the explanation of the all-or-none spike according to the Modern Ionic Hypothesis.

Figure 5—Hodgkin-Huxley representation of small area of axon membrane

Figure 6—Typical responses of sodium conductance and potassium conductance to imposed step depolarization

By defining the net driving force on any given ion species as the difference between the membrane potential and the equilibrium potential for that ion and describing permeability changes in terms of equivalent electrical conductance changes, Hodgkin and Huxley reduced the ionic model to the electrical equivalent in [Figure 5]. The important dynamic variables in this equivalent network are the sodium conductance (G{Na}) and the potassium conductance (G{K}). The change in the sodium conductance in response to a step depolarization is shown in [Figure 6B]. This change can be characterized by seven voltage dependent parameters:

1. Delay time—generally much less than 1 msec

2. Rise time—1 msec or less

3. Magnitude of peak conductance—increases monotonically with increasing depolarization

4. Inactivation time constant—decreases monotonically with increasing depolarization.

5. Time constant of recovery from inactivation—incomplete data

6. Magnitude of steady-state conductance—increases monotonically with increasing depolarization

7. Fall time on sudden repolarization—less than 1 msec.

[Figure 6B] shows the potassium conductance change in response to an imposed step depolarization. Four parameters are sufficient to characterize this response:

1. Delay time—decreases monotonically with increasing depolarization

2. Rise time—decreases monotonically with increasing depolarization

3. Magnitude of steady-state conductance—increases monotonically with increasing depolarization

4. Fall time on sudden repolarization—8 msec or more, decreases slightly with increasing depolarization.

In addition to the aforementioned parameters, the transient portion of the sodium conductance appears to exhibit an accommodation to slowly varying membrane potentials. The time constants of accommodation appear to be those of inactivation or recovery from inactivation—depending on the direction of change in the membrane potential [(18)]. The remaining elements in the Hodgkin-Huxley model are constant and are listed below: