Action Potentials and Ion Channel Mechanics in Neurophysiology

The opening of these channels creates a positive feedback loop: the influx of $\text{Na}^+$ causes further depolarization, which in turn triggers even more voltage-gated $\text{Na}^+$ channels to open.

Repolarization and Hyperpolarization via $\text{K}^+$ Channels

While $\text{Na}^+$ channels drive the rising phase of the action potential, voltage-gated $\text{K}^+$ channels are responsible for returning the membrane to its resting state.

These channels behave differently than $\text{Na}^+$ channels; they open with a slight delay in response to depolarization. As $\text{K}^+$ ions flow out of the cell, the membrane undergoes repolarization, moving the membrane potential back toward a negative value.

Because these $\text{K}^+$ channels close relatively slowly, the outward flow of potassium often continues even after the resting potential has been reached. This leads to hyperpolarization, where the membrane potential becomes even more negative, moving closer to the potassium equilibrium potential ($E_{\text{K}}$).

Refractory Periods: Ensuring Directional Flow

The timing of these channel movements creates two distinct refractory periods that limit how many action potentials a neuron can fire in a given time:

• Absolute Refractory Period: During the peak of the action potential, $\text{Na}^+$ channels are either already open or are in an inactivated state. During this time, no second action potential can be generated, no matter how strong the stimulus.
• Relative Refractory Period: As some $\text{Na}^+$ channels begin to reset to their closed (but ready) state, a second action potential becomes possible, but only if the stimulus is significantly stronger than usual.

These periods are crucial because they ensure that action potentials are propagated in only one direction down the axon.

Neuron Excitability and Ion Concentrations

The ease with which a neuron can fire an action potential—its excitability—is heavily influenced by the concentration of ions in the extracellular fluid (ECF).

Extracellular Potassium ($\text{[K}^+\text{]}_{\text{ECF}}$)

Potassium levels have a complex, non-linear effect on excitability:

• Moderate Increase ($3.5\text{--}6\text{ mM}$): This depolarizes the membrane potential, moving it closer to the threshold and making the neuron more excitable.
• High Levels ($>6\text{ mM}$): Paradoxically, very high potassium levels can reduce excitability. This occurs because the persistent depolarization keeps the voltage-gated $\text{Na}^+$ channels in their inactivated state, preventing them from resetting.

Extracellular Calcium ($\text{[Ca}^{++}\text{]}_{\text{ECF}}$)

Calcium ions play a regulatory role by binding to the external surfaces of $\text{Na}^+$ channels.

• Hypocalcemia (Low $\text{Ca}^{++}$): Increases membrane excitability.
• Hypercalcemia (High $\text{Ca}^{++}$): Reduces membrane excitability.

Summary of the Action Potential Cycle

To visualize the entire process, we can track the membrane potential through these stages:

1. Resting State: The membrane is near the potassium equilibrium potential due to leak channels.
2. Depolarization: A stimulus reaches the threshold voltage, opening $\text{Na}^+$ activation gates and triggering a positive feedback loop.
3. Repolarization: $\text{Na}^+$ inactivation gates close, and delayed $\text{K}^+$ channels open, allowing $\text{K}^+$ to exit the cell.
4. Hyperpolarization: Slow $\text{K}^+$ channel closure drives the potential toward $E_{\text{K}}$.
5. Reset: $\text{K}^+$ channels close, and $\text{Na}^+$ channels reset from the inactivated state to the closed state, returning the cell to its resting potential.