The action potential ($\text{AP}$) in a nerve fiber is a rapid, transient electrical signal essential for long-distance communication in the nervous system.

Definition of the Action Potential

The action potential is defined as a rapid and transient depolarization of the membrane potential (Vm) in electrically excitable cells, such as neurons. It is a transient, regenerative electrical impulse in which the membrane potential rapidly rises to a peak that is typically approximately 100 mV more positive than the normal negative resting voltage (Vrest). Because of its sharp, pointy appearance, the AP is often referred to as a "spike" or a "nerve impulse".

The AP is caused by a sudden, selective alteration in the membrane's permeability to small ions. In nerve axons, this alteration involves a rapid increase in permeability to Na+ ions, followed by a decrease in Na+ permeability and an increase in K+ permeability.

Phases and Ionic Basis of the Action Potential in a Nerve Fiber

The nerve AP is generated primarily by the activity of voltage-gated Na+ and K+ channels. The process is a cyclical sequence of channel opening and closing.

Resting Membrane Potential (Vrest)

Stable negative potential, typically around -70 mV in nerve.

High permeability/conductance to K+ ions through leak channels, driving Vm close to the K+ equilibrium potential (E K approx -85 mV to -90 mV). Na+ conductance is very low.

The voltage-gated Na+ channel is in the "closed, but available" state (activation gate closed, inactivation gate open).

Depolarization to Threshold

Vm shifts from Vrest toward a critical level, the threshold potential (typically around -60 mV or -55 mV in nerve).

Initial inward current (I inward).

Small depolarizing stimuli cause local changes (catelectrotonus). If the depolarization reaches threshold, net inward current (I Na) becomes larger than net outward current (I K), making the depolarization self-sustaining.

Upstroke / Rapid Depolarization

Vm rapidly rises from threshold to a positive peak (overshoot), typically around +30 mV or +40 mV.

Massive, rapid increase in Na+ conductance (gNa). This generates a large **inward Na+ current (I Na)**, driving Vm toward the Na+ equilibrium potential (E Na approx +65 mV).

Activation gates of Na+ channels open quickly. This is a positive feedback mechanism: depolarization opens Na+ channels, increasing I Na, causing further depolarization.

Repolarization (Falling Phase)

Vm rapidly returns to the resting potential.

Na+ conductance falls, and K+ conductance (g K) increases significantly. This generates a large **outward K+ current (I K)**, driving Vm back toward E K.

Inactivation gates of Na+ channels close slowly during the upstroke, terminating I Na (Na+ channel inactivation). Concurrently, voltage-gated K+ channels open (delayed activation).

After-hyperpolarization (Undershoot)

V m briefly becomes more negative than V rest. K+ conductance remains higher than at rest. The outward $\text{K}^{+}$ current drives $\text{V}{\text{m}}$ even closer to E K. Voltage-gated K+ channels slowly close. The membrane recovers excitability.

The entire nerve AP lasts only about 1 to 2 milliseconds (msec).

Properties of the Action Potential

Action potentials possess several characteristic properties:

1. All-or-None Response: An $\text{AP}$ either occurs fully or not at all. Once the threshold voltage is reached, the AP is inevitable and its amplitude and time course are independent of the stimulus strength.

2. Stereotypical Size and Shape: For a given nerve cell type, all normal APs look identical in amplitude and time course.

3. Propagation (Conduction without Decrement): The AP is transmitted along the axon at full amplitude (without loss of size or decrement) over long distances.

   • Mechanism: Propagation occurs because an active patch of membrane undergoing the upstroke acts as a source of local stimulus current for the adjacent resting membrane. This local current flow depolarizes the adjoining region to threshold, causing a new AP to be generated there, regenerating the signal continuously.

   • In Unmyelinated Axons: APs are produced along the entire length of the axon as a continuous wave of excitation.

   • In Myelinated Axons (Saltatory Conduction): Conduction is much faster. Na+ channels are concentrated at the nodes of Ranvier, which are periodic breaks in the insulating myelin sheath. The AP appears to "jump" from node to node, propagating by the electrotonic spread of local circuit currents across the high-resistance, low-capacitance internodal region.

4. Refractory Periods: A period during which the nerve is unable to produce a normal AP in response to a stimulus.

   • Absolute Refractory Period (ARP): Lasts from the initiation of the spike until repolarization is almost complete. A second AP cannot be elicited regardless of the stimulus strength. This is due to the inactivation gates of Na+ channels being closed and unavailable.

   • Relative Refractory Period (RRP): Follows the ARP until Vm returns to V rest. A stronger than normal stimulus is required to initiate a second $\text{AP}$. This is because K+ conductance is still higher than at rest, and the membrane potential is farther from the threshold, requiring more inward current.

5. Coding of Stimulus Strength: Since APs are all-or-none, stimulus strength is encoded by the frequency (number per second) of the APs generated (frequency modulated, FM).

6. Conduction Velocity (CV): The speed of propagation is determined by two cable properties: the length constant (lambda) and the time constant (tau_m). CV is increased by:

   • Increased Fiber Diameter: A larger diameter reduces internal resistance, increasing the length constant (lambda), thus allowing local currents to spread farther to trigger the next AP.

   • Myelination (Saltatory Conduction): Myelin increases membrane resistance and decreases membrane capacitance, resulting in a large lambda and a short tau_m, dramatically increasing CV.

Applied Clinical Aspects of Action Potential

Disruptions in nerve action potential generation, propagation, or transmission are the basis for several clinical pathologies and pharmacological interventions:

1. Neurological Disorders (Conduction Failure)

• Demyelinating Diseases (e.g., Multiple Sclerosis): Loss of the myelin sheath in the CNS increases membrane capacitance and decreases membrane resistance in the internodal region. This reduces the effectiveness of local circuit currents, meaning the current generated at one node may be insufficient to depolarize the next node to threshold, resulting in conduction failure. Symptoms like paralysis and altered sensation array from demyelination and are attributed to this failure of action potential transmission.

• Hyperkalemic Periodic Paralysis: This condition involves a temporary weakness or paralysis due to a Na+ channel defect where high K+ interferes with channel inactivation.

• Hyperkalemia (increased K+ ecf): High extracellular K+ concentration depolarizes the resting membrane potential. Although this moves V_m closer to threshold, sustained depolarization causes the inactivation gates of Na+ channels to close. This reduction in available Na+ channels decreases excitability, leading to muscle weakness.

2. Diagnostic Testing

• Nerve Conduction Studies (NCS): These are techniques used to record, measure, and interpret APs in peripheral nerves and muscles (EMG). Measuring conduction velocity and latency provides early and accurate diagnoses for conditions like nerve injuries, neuropathies (e.g., in diabetes mellitus), vitamin deficiencies, and demyelination.

• Electromyography (EMG): Records the sum of APs in muscle fibers (Motor Unit Potential, MUP) during voluntary contraction.

3. Pharmacological Interventions

• Local Anesthetics: These agents, such as lidocaine, procaine, and cocaine, block Na+ channels. By blocking a fraction of Na+ channels, they decrease the magnitude of the Na+ current, resulting in an AP with a higher threshold, a slower rate of rise, and a lower peak amplitude. They reversibly bind to Na+ channels, preventing them from opening to produce depolarization.

• Toxins: Certain toxins selectively target voltage-gated channels, altering the AP.

  • Na+ Channel Blockers: Tetrodotoxin (TTX) and Saxitoxin (STX) are highly selective blockers of voltage-gated Na+ channels. Blocking these channels decreases the Na+ current, affecting AP characteristics similarly to local anesthetics.

  • K+ Channel Blockers: Tetraethylammonium ions (TEA) block voltage-gated K+ channels. Blocking the outward K+ current prevents or slows repolarization, thereby prolonging the AP duration. Dendrotoxins also inhibit repolarization by blocking K+ channels.

• Anticonvulsants/Antiarrhythmics: Many drugs used to stabilize the nervous system or cardiac excitability work by modulating Na+ channel inactivation or recovery kinetics.

Based on the provided sources, the drugs and toxins known to inhibit or block voltage-gated sodium (Na+) channels and voltage-gated potassium (K+) channels are listed below.

I. Inhibitors of Voltage-Gated Sodium (Na+) Channels (Na_V)

These agents typically block the flow of Na+ ions through the channel pore, or impede the channel's normal gating functions:

Agent Category

Specific Examples

Mechanism of Action

Guanidinium Toxins (Selective Blockers)

Tetrodotoxin (TTX) (puffer fish poison)

Highly selective blocker of voltage-gated Na+ channels, acting on the extracellular side with high affinity, occluding the channel pore.

Saxitoxin (STX) (dinoflagellate toxin, causing red tide)

Highly selective blocker of voltage-gated Na+ channels, similar to TTX, acting on the extracellular side.

Peptide Toxin

micro Conotoxin (marine snail venom)

Blocks muscle Na+ channels (Nav1.4) by binding near the external binding site for TTX and STX.

Local Anesthetics (Drugs)

Local anesthetics (general class)

Block Na+ channels.

Lidocaine (a local anesthetic)

Blocks voltage-sensitive Na+ channels and abolishes action potentials (APs).

Cocaine and Procaine

Examples of local anesthetics that reversibly bind to Na+ channels in the axon membrane, preventing them from opening to produce depolarization.

Toxins Interfering with Inactivation (Modulators)

Sea anemone toxin

Reduces the rate of Na+ channel inactivation, thereby prolonging the duration of the AP.

Batrachotoxin (steroidal alkaloid)

Acts by altering the gating kinetics of Na+ channels, promoting a longer duration of channel opening and opening under normally inactivated conditions.

Plant alkaloids (veratridine, grayanotoxin, aconitine)

Act by altering the gating kinetics of Na+ channels by promoting both a longer duration of channel opening and channel opening under voltage conditions in which Na+ channels are normally closed or inactivated. 

Pyrethrins (natural plant insecticides)

Act by altering the gating kinetics of Na+ channels.

Brevetoxins (cyclic polyethers)

Act by altering the gating kinetics of Na+ channels.

Scorpion toxins (two peptide classes)

Act by altering the gating kinetics of Na+ channels.

II. Inhibitors of Voltage-Gated Potassium (K+) Channels (K_V)

These agents block the outward K+ current, which is responsible for the repolarization phase of the action potential:

Agent Category

Specific Examples Cited in Sources

Mechanism of Action

Quaternary Ammonium Ions (Blockers)

Tetraethylammonium ions (TEA)

Blocks voltage-gated K+ channels. TEA inhibits the outward K+ current, thereby prolonging the duration of the AP.

Aminopyridines (Blockers)

4-aminopyridine (4-AP) or Aminopyridines

Inhibits many transient A-type K+ currents (K_A channels). Blocking these channels can prolong the spike, which may facilitate propagation through demyelinated axons.

Toxins (Selective Blockers)

Dendrotoxin (mamba snake venom)

Blocks certain isoforms of voltage-gated K+ channels by binding to an extracellular site in the P-region domain. Blockade inhibits repolarization of the presynaptic membrane.

Charybdotoxins (scorpion venom)

Peptide toxins that can discriminate particular subtypes of K_V channels (and Ca 2+ - activated K+ channels).

Other K+ Channel Related Inhibitors (K-ATP)

Sulfonylureas (Tolbutamide, Glibenclamide)

Selectively block K_ATP channels, which are members of the inward-rectifier K+ channel family, leading to depolarization.