Medical School · Year 1 · Physiology · includes a quiz and discussion video

Lecture 2: Action Potential and Nerve Conduction

Unit 1.6: Physiology Foundations

Learning Objectives

By the end of this lecture, students will be able to:

1. Describe the phases of the action potential and their ionic basis
2. Explain the concepts of threshold, all-or-none response, and refractory periods
3. Describe the mechanisms of action potential propagation
4. Compare saltatory and continuous conduction
5. Explain factors affecting nerve conduction velocity
6. Apply these concepts to clinical conditions affecting nerve function

Overview of Action Potentials

The action potential represents the fundamental unit of rapid electrical signaling in the nervous system and muscle. Unlike the passive spread of graded potentials that decays with distance, the action potential regenerates itself along the membrane, propagating without decrement from its point of origin to the axon terminals. This self-propagating electrical signal enables communication across the substantial distances separating the central nervous system from peripheral targets.

Several characteristics define the action potential and distinguish it from other electrical signals. The amplitude of approximately 100 mV (from a resting potential of -70 mV to a peak of +30 mV) remains constant regardless of stimulus strength. The duration in typical neurons spans only 1-2 milliseconds, allowing rapid repetitive firing. The all-or-none nature means that any stimulus reaching threshold produces a full action potential, while subthreshold stimuli produce only local graded responses that decay with distance. This non-decremental propagation ensures that signals arrive at distant targets with the same amplitude and information content as at their origin.

Graded potentials contrast with action potentials in important ways. Receptor potentials generated by sensory stimuli and synaptic potentials at postsynaptic membranes exhibit variable amplitude proportional to stimulus strength. These potentials decay exponentially with distance from their source because they spread passively through the cytoplasm. While graded potentials cannot transmit information over long distances themselves, they integrate at the axon hillock to determine whether an action potential will be generated.

<image>Panel A: Graded potentials showing variable amplitude responses proportional to stimulus strength with rounded waveforms. Panel B: Exponential decay of graded potentials with increasing distance from the stimulation point. Panel C: Action potentials as uniform sharp spikes reaching the same peak regardless of stimulus strength above threshold. Panel D: Non-decremental propagation of action potentials maintaining constant amplitude along the axon.</image>

Phases of the Action Potential

The action potential proceeds through distinct phases, each characterized by specific ion channel states and ionic currents. Understanding these phases provides the foundation for comprehending how neurons encode and transmit information.

During the resting phase, the membrane potential remains stable at approximately -70 mV. Voltage-gated sodium channels exist in the closed state, with their activation gates shut but ready to respond to depolarization. Some potassium channels (leak channels) remain open, maintaining membrane permeability predominantly to potassium. This potassium permeability keeps the resting potential near the potassium equilibrium potential.

The depolarization phase (rising phase) begins when a stimulus depolarizes the membrane to threshold, typically around -55 mV. At this critical voltage, the probability of voltage-gated sodium channels opening exceeds the probability of remaining closed. Sodium channel opening allows sodium influx down its electrochemical gradient, causing further depolarization that opens additional sodium channels. This positive feedback loop produces rapid, explosive depolarization that drives the membrane potential toward the sodium equilibrium potential of +61 mV, though the peak typically reaches only about +30 mV before inactivation occurs.

The repolarization phase (falling phase) begins within about 0.5 milliseconds as two processes combine to reverse depolarization. Voltage-gated sodium channels inactivate—a process distinct from closing, where an inactivation gate swings into the channel pore, blocking further sodium entry regardless of activation gate status. Simultaneously, voltage-gated potassium channels, which opened more slowly during depolarization, now conduct potassium efflux that drives the membrane back toward the potassium equilibrium potential.

The hyperpolarization phase (undershoot) occurs because potassium channels remain open after the membrane has returned to resting potential, continuing to drive hyperpolarization to approximately -80 to -90 mV. The eventual closing of these potassium channels, combined with ongoing Na⁺/K⁺-ATPase activity that restores ion gradients, returns the membrane to its resting state.

<image>Panel A: Action potential waveform showing the characteristic spike from resting potential through depolarization peak and repolarization. Panel B: Resting and depolarization phases with sodium channel activation gates opening and rapid sodium influx. Panel C: Repolarization phase showing sodium channel inactivation and delayed potassium channel opening with potassium efflux. Panel D: Hyperpolarization undershoot phase with continued potassium efflux and sodium channel recovery from inactivation.</image>

Ionic Basis of the Action Potential

Voltage-gated sodium channels possess a dual-gate mechanism that explains the rapid activation and subsequent inactivation characteristic of the action potential. The activation gate (m gate) responds quickly to depolarization, swinging open within a fraction of a millisecond. The inactivation gate (h gate) responds more slowly, closing several milliseconds after the activation gate opens. The channel conducts only when both gates are open—a condition that exists briefly during the rising phase before the inactivation gate closes.

The recovery from inactivation requires membrane repolarization. When the membrane returns toward resting potential, the inactivation gate reopens (deinactivates), but only while the activation gate simultaneously returns to its closed position. This sequence ensures that the channel must pass through the closed, ready state before it can reopen, providing the refractory period necessary for unidirectional propagation.

Voltage-gated potassium channels demonstrate simpler kinetics with a single gate that opens slowly during depolarization. This delayed activation means potassium channels reach their maximum open probability after sodium channels have already begun inactivating. The potassium channels continue conducting during repolarization and into the hyperpolarization phase, closing only after the membrane has overshot its resting potential.

The different kinetics of sodium and potassium channels create the action potential waveform. Fast sodium activation produces the rapid upstroke; sodium inactivation halts depolarization at the peak; delayed potassium activation produces repolarization; prolonged potassium activation causes hyperpolarization.

<image>Panel A: Sodium channel two-gate model showing transitions between closed-ready, open-conducting, inactivated, and closed-recovering states. Panel B: Potassium channel simpler gating with closed and open states and slower transition kinetics. Panel C: Overlapping time courses of sodium and potassium conductance during the action potential. Panel D: Resulting membrane potential changes from the combined ionic currents showing the action potential waveform.</image>

Threshold and All-or-None Response

Threshold represents the membrane potential at which action potential initiation becomes self-sustaining, typically around -55 mV in most neurons. At this critical voltage, inward sodium current exceeds outward potassium current, creating net positive charge entry that further depolarizes the membrane. This depolarization opens more sodium channels, increasing sodium current in a positive feedback loop that drives the explosive upstroke of the action potential.

Subthreshold stimuli fail to initiate action potentials because they cannot generate sufficient sodium channel opening to overcome the stabilizing influence of potassium conductance. These stimuli produce local depolarizations that decay exponentially with distance and time. However, subthreshold stimuli can summate if they occur close together in space (spatial summation) or time (temporal summation), potentially reaching threshold through their combined effect.

The all-or-none principle states that once threshold is reached, the action potential proceeds to completion with its full amplitude. Increasing stimulus strength beyond threshold does not produce larger action potentials because the positive feedback mechanism drives the membrane toward the same sodium equilibrium potential regardless of the triggering stimulus. A stimulus either exceeds threshold and produces a full action potential or fails to reach threshold and produces only a local response.

Since action potential amplitude cannot encode stimulus intensity, neurons use frequency coding instead. Stronger stimuli produce higher frequencies of action potentials, while weaker stimuli produce lower frequencies. The nervous system interprets higher firing rates as more intense stimuli, whether for sensory perception, motor activation, or any other modality.

<image>Panel A: Subthreshold stimulus producing local graded response that decays without generating an action potential. Panel B: Threshold and suprathreshold stimuli both producing identical amplitude action potentials demonstrating the all-or-none principle. Panel C: Frequency coding showing weak stimuli producing low firing rates and strong stimuli producing high firing rates. Panel D: Stimulus intensity correlation with action potential frequency while maintaining uniform spike amplitude.</image>

Refractory Periods

Refractory periods limit the maximum frequency of action potential firing and ensure unidirectional propagation along axons. The absolute refractory period occurs during the time when voltage-gated sodium channels are either open or inactivated and cannot be reopened regardless of stimulus strength. This period typically lasts 1-2 milliseconds and corresponds to the depolarization phase through early repolarization. No stimulus, regardless of intensity, can trigger another action potential during this interval.

The relative refractory period follows the absolute refractory period and corresponds to the hyperpolarization phase when some sodium channels have recovered from inactivation but potassium channels remain open. During this period, a stronger-than-normal stimulus can trigger an action potential, but the resulting action potential may have reduced amplitude because fewer sodium channels are available and potassium conductance is elevated. This period lasts several milliseconds after the absolute refractory period.

These refractory periods have important physiological consequences. Maximum firing frequency is limited to approximately 500-1000 action potentials per second, determined primarily by the duration of the absolute refractory period. Additionally, refractory periods ensure unidirectional propagation along axons. When an action potential depolarizes adjacent membrane regions, the membrane behind the action potential cannot respond because it remains in its refractory period from the just-completed action potential. Only the membrane ahead, which has been at rest, can respond to the depolarizing current, ensuring forward propagation.

<image>Panel A: Complete action potential trace showing the characteristic voltage changes from resting through depolarization, repolarization, and hyperpolarization. Panel B: Absolute refractory period during depolarization and early repolarization when no stimulus can trigger another action potential. Panel C: Relative refractory period during hyperpolarization when stronger than normal stimuli are required to trigger an action potential. Panel D: Sodium and potassium channel states during each refractory period showing inactivation and recovery processes.</image>

Action Potential Propagation

Action potentials propagate along axons through local circuit currents that depolarize adjacent membrane regions to threshold. When a segment of membrane generates an action potential, positive charges (sodium ions) entering at that location spread in both directions along the axoplasm. This current flow depolarizes the adjacent resting membrane, bringing it toward threshold. Once threshold is reached, that adjacent segment generates its own action potential, which in turn depolarizes the next segment. This process repeats sequentially along the axon.

Continuous conduction occurs in unmyelinated axons, where action potentials must be regenerated at each point along the membrane. Because every portion of the membrane contains voltage-gated channels and must depolarize to threshold, conduction velocity is relatively slow (0.5-2 m/s). The energy cost of continuous conduction is high because ion fluxes occur along the entire length of the axon, requiring substantial Na⁺/K⁺-ATPase activity to restore gradients.

Saltatory conduction occurs in myelinated axons and dramatically increases both conduction velocity and energy efficiency. Myelin, formed by oligodendrocytes in the central nervous system and Schwann cells in the peripheral nervous system, wraps around axon segments and acts as an electrical insulator. This insulation prevents ion flux across myelinated regions and forces current to flow along the axoplasm to the next node of Ranvier—small gaps in the myelin where the axon membrane is exposed.

Nodes of Ranvier contain extremely high densities of voltage-gated sodium channels, enabling action potential regeneration at these sites. Current flowing from an active node depolarizes the next node rapidly because the myelinated internode acts as an efficient cable, with minimal current loss through the insulated membrane. The action potential appears to "jump" from node to node, hence the term saltatory (from Latin "saltare," to jump). This mechanism increases conduction velocity to as high as 120 m/s while reducing energy expenditure because ion exchange occurs only at nodes.

<image>Panel A: Continuous conduction in unmyelinated axons showing sequential membrane activation with slow conduction velocity of 0.5-2 m/s. Panel B: Local current flow patterns in continuous conduction with active, depolarizing, and refractory regions along the axon. Panel C: Saltatory conduction in myelinated axons with action potentials jumping between nodes of Ranvier at velocities up to 120 m/s. Panel D: Node of Ranvier structure showing high sodium channel density and current flow through myelinated internodes to the next node.</image>

Factors Affecting Conduction Velocity

Axon diameter significantly influences conduction velocity because it determines the internal resistance to current flow. Larger diameter axons have lower internal resistance, allowing faster spread of local currents and more rapid depolarization of distant membrane segments. This relationship explains why rapid-response systems such as motor pathways and proprioceptive afferents use large-diameter axons. In invertebrates lacking myelination, giant axons (up to 1 mm in diameter in squid) evolved to achieve rapid escape responses.

Myelination increases conduction velocity through the mechanism of saltatory conduction described above. The combination of reduced membrane capacitance (because current cannot accumulate on myelinated segments) and increased length constant (because current spreads farther before decaying) enables rapid, efficient propagation. Demyelinating diseases dramatically reduce conduction velocity and can cause conduction block when action potentials fail to bridge the now-exposed internodal regions.

Temperature affects conduction velocity by altering channel kinetics and membrane properties. Within physiological ranges, higher temperatures increase conduction velocity by accelerating the conformational changes in voltage-gated channels. Cooling slows conduction, and sufficient cooling can block conduction entirely. This phenomenon has clinical applications: cooling peripheral nerves produces reversible anesthesia, and induced hypothermia during cardiac surgery protects the nervous system by reducing metabolic demands and slowing harmful processes.

Nerve fiber classification organizes axons by diameter, myelination status, and conduction velocity, correlating with specific functions. Type Aα fibers (12-20 μm diameter, myelinated, 70-120 m/s) carry proprioception and motor commands requiring the fastest conduction. Type Aβ fibers (5-12 μm, 30-70 m/s) carry touch and pressure sensation. Type Aδ fibers (2-5 μm, 12-30 m/s) carry fast pain and temperature sensation. Type B fibers (less than 3 μm, 3-15 m/s) carry preganglionic autonomic signals. Type C fibers (0.5-2 μm, unmyelinated, 0.5-2 m/s) carry slow pain, temperature, and postganglionic autonomic signals.

<image>Panel A: Cross-sectional comparison of nerve fiber types showing relative axon diameters from large myelinated A-alpha fibers to small unmyelinated C fibers. Panel B: Conduction velocity ranges for each fiber type correlating with diameter and myelination status. Panel C: Primary sensory and motor functions associated with each fiber classification. Panel D: Relationship between axon diameter and conduction velocity showing linear relationship in myelinated fibers and square-root relationship in unmyelinated fibers.</image>

Compound Action Potential

The compound action potential represents the summed electrical activity of all axons within a peripheral nerve responding to a stimulus. Unlike the all-or-none response of individual axons, the compound action potential is graded because different axons within the nerve have different thresholds and respond at different stimulus intensities. Increasing stimulus strength recruits additional axons, increasing the amplitude of the compound response until all axons in the nerve are activated.

The waveform of the compound action potential shows distinct components corresponding to different fiber types. The A wave, appearing first and with the largest amplitude, reflects the contribution of large myelinated fibers conducting most rapidly. Within the A wave, subcomponents (α, β, γ, δ) can sometimes be distinguished. The B wave follows, representing smaller myelinated preganglionic autonomic fibers. The C wave arrives last and often has lower amplitude, reflecting the slow-conducting unmyelinated fibers. The temporal separation of these waves increases with distance from stimulation because velocity differences accumulate over distance.

Nerve conduction studies exploit these principles for clinical diagnosis. By stimulating a nerve at known distances from recording electrodes and measuring the latency (time to response) and amplitude, clinicians can calculate conduction velocity and assess the number of functioning axons. Demyelinating conditions such as Guillain-Barré syndrome produce prolonged latencies and slowed conduction velocities while preserving amplitude early in the disease course. Axonal disorders such as diabetic neuropathy reduce amplitude because fewer axons contribute to the compound action potential. These electrodiagnostic studies help distinguish between demyelinating and axonal pathology and guide treatment decisions.

<image>Panel A: Compound action potential waveform showing A wave from large myelinated fibers, B wave from smaller myelinated fibers, and C wave from unmyelinated fibers. Panel B: Recording setup with stimulating and recording electrodes at measured distance along the nerve. Panel C: Normal nerve conduction study findings with expected latency and amplitude values. Panel D: Abnormal patterns comparing demyelinating neuropathy with prolonged latency versus axonal neuropathy with reduced amplitude.</image>

Clinical Applications

Local anesthetics block nerve conduction by binding to and inactivating voltage-gated sodium channels, preventing the depolarization necessary for action potential generation. These agents demonstrate use-dependent block, binding preferentially to channels that are open or inactivated rather than resting; this means that more actively firing nerves are blocked more effectively. Clinically, small unmyelinated C fibers (carrying pain) are blocked before larger myelinated fibers (carrying motor and touch) due to their higher firing rates and the safety margin of large-fiber saltatory conduction. Common agents include lidocaine, bupivacaine, and procaine.

Multiple sclerosis exemplifies the clinical consequences of central nervous system demyelination. Autoimmune destruction of oligodendrocyte myelin leaves axons exposed, causing conduction slowing and block. The patchy distribution of demyelination produces varied symptoms affecting motor, sensory, and visual pathways depending on lesion location. Symptoms may temporarily worsen with elevated body temperature (Uhthoff phenomenon) because heat further impairs conduction in marginally functioning demyelinated fibers. Diagnosis combines clinical findings with MRI demonstration of white matter lesions and evoked potential studies showing delayed conduction.

Guillain-Barré syndrome produces acute peripheral nervous system demyelination through autoimmune attack on Schwann cells. Classically presenting as ascending weakness beginning in the legs and progressing upward, this condition can compromise respiratory function if thoracic and cervical nerves are affected. Nerve conduction studies show prolonged distal latencies, slowed conduction velocities, and temporal dispersion of compound action potentials. Recovery occurs with remyelination, though residual deficits may persist.

Channelopathies are genetic disorders affecting ion channel function that produce diverse clinical phenotypes. Hyperkalemic periodic paralysis results from gain-of-function mutations in voltage-gated sodium channels that impair inactivation, causing sustained depolarization and paradoxical weakness when extracellular potassium rises. Myotonia congenita results from chloride or sodium channel mutations that cause prolonged muscle contraction due to repetitive firing. Long QT syndrome results from potassium or sodium channel mutations that prolong cardiac action potential duration, predisposing to life-threatening arrhythmias.

<image>Panel A: Local anesthetic mechanism showing lidocaine binding to sodium channel inner pore region blocking sodium influx during open and inactivated states. Panel B: Multiple sclerosis pathology with patchy CNS demyelination causing conduction failure at exposed axon segments. Panel C: Guillain-Barré syndrome showing peripheral nerve Schwann cell injury with myelin stripping and nerve conduction abnormalities. Panel D: Channelopathies including periodic paralysis from impaired sodium channel inactivation and Long QT syndrome with prolonged cardiac action potentials.</image>

Summary

Action potentials are all-or-none, non-decremental electrical signals that propagate along excitable membranes. The depolarization phase results from rapid sodium influx through voltage-gated sodium channels, while repolarization results from sodium channel inactivation combined with delayed potassium efflux. Threshold (approximately -55 mV) represents the membrane potential at which sodium influx exceeds potassium efflux, initiating the positive feedback loop of action potential generation. Information about stimulus intensity is encoded in action potential frequency rather than amplitude.

Refractory periods limit maximum firing frequency and ensure unidirectional propagation. The absolute refractory period, during which no stimulus can trigger an action potential, corresponds to sodium channel inactivation. The relative refractory period requires stronger stimuli due to partial sodium channel recovery and elevated potassium conductance.

Saltatory conduction in myelinated axons dramatically increases conduction velocity and energy efficiency compared to continuous conduction in unmyelinated axons. Conduction velocity also depends on axon diameter and temperature. Clinical conditions affecting nerve conduction include local anesthetic blockade, demyelinating diseases such as multiple sclerosis and Guillain-Barré syndrome, and ion channel mutations causing channelopathies.

Key Terms

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