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PhysiologyNervous systemAction potential and synapsesRefractory periods
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PhysiologyNervous systemAction potential and synapsesRefractory periods

Refractory periods

Author: Maria Vasileiou • Reviewer: Assist. Prof. Konstantinos Ι. Tsamis, MD
Last reviewed: April 24, 2024
Reading time: 11 minutes

A refractory period refers to a specific duration in which an organ or cell is unable to repeat an activity. For excitable cells like neurons and muscle fibers, refractory period is the time interval required to recover from an action potential before generating the next one.

It is subdivided into the absolute and relative refractory periods, primarily determined by the activity of voltage-gated sodium channels, with voltage-gated potassium channels also playing a role. The refractory period is crucial for ensuring the unidirectional propagation of the electrical impulse and regulating the frequency of signal transmission.

Key facts about refractory periods
Definition For neurons and muscle fibers, the refractory period is the time interval required to recover from an action potential before generating the next one.
Subphases Absolute refractory period: Spans from the depolarization phase to the initial repolarization phase of the action potential.

Relative refractory period: Spans from the late repolarization phase to the hyperpolarization phase of the action potential.
Voltage-gated ion channels involved Voltage-gated Na+ channels:
- Two gates
- Fast activation

Voltage-gated K+ channels:
- One gate
- Slow activation
Roles -Securing forward propagation of signals
-Distinguishing action potential from graded potentials
-Preventing overstimulation
-Regulating signal transmission frequency.

Action potential

For a standard neuron, the initiation of an action potential occurs when the sum of incoming stimuli surpasses the threshold at the axon hillock. The resting potential for nerve fibers typically lies around -70mV, while the threshold required to trigger an action potential is at -55mV.

The stimuli leading to an action potential involve an accumulation of sodium ions within the cell, depolarizing the membrane, and eventually reaching the critical potential of -55mV. At this threshold, according to the all-or-none law, an electrical impulse is generated, propagating along the axon from the trigger zone to the nerve endings. This action potential is characterized by three distinct phases (depolarization, repolarization and hyperpolarization) and depends vastly on the activity of voltage-gated ion channels.

Action potential phases

  1. Depolarization: This is the initial phase of the action potential and starts when the previously resting membrane potential reaches the threshold level at-55mV. As the concentration of sodium ions increases intracellularly, the cytosolic side of the membrane undergoes increasing positivity, reaching a peak of +30mV. This is the peak voltage of the membrane potential. At this moment depolarization is completed and the subsequent repolarization phase has commenced.
  2. Repolarization: This is the second phase of the action potential, where the membrane aims to return to the resting state. Starting from the +30mV voltage point, repolarization corresponds with the restoration of the membrane potential to -70mV through the movement of ions across the membrane.
  3. Hyperpolarization: As the membrane potential returns to -70mV, the previously open ion channels require a period to revert to their initial conformation. During this interval, certain cations continue to exit the neuron, resulting in an accumulation of negative charge within the cell. Consequently, the membrane potential can drop to -90mV before eventually reverting to its resting state of -70mV. This phase of increased negativity across the cytosolic side of the membrane is termed hyperpolarization.

Role of voltage-gated ion channels

Voltage-gated sodium channels are integral membrane proteins predominantly found in the trigger zone and along the entire length of the axon, which are crucial regions for the initiation and propagation of action potentials. These channels demonstrate remarkable sensitivity and rapid responsiveness to changes in membrane potential, directly influencing the refractory period of neurons.

Comprising activation and inactivation gates that govern the permeability of the channel pore, voltage-gated sodium channels have three distinct conformational states.

Voltage-gated potassium channels are transmembrane proteins that regulate the passage of potassium ions through the membrane. Operating with a single gate, they become activated during the depolarization phase. Due to their delayed response to activation, these channels open their lumen at a membrane potential of +30mV, only after the membrane potential has reached its peak. They affect the refractory period by dominating the repolarization phase. The activation of the voltage-gated potassium channels coincides with inactivation of the voltage-gated sodium channels.

Absolute refractory period

From the onset of depolarization until the initial stages of repolarization, it is impossible for a neuron or muscle fiber to generate a second impulse, regardless of the strength of the stimulus.

This phase marks the absolute refractory period. It begins when the initial depolarization of the membrane reaches the threshold at -55mV, instantly activating the voltage-gated sodium channels. This allows sodium ions to enter the cell, further depolarizing the specific part of the membrane and coinciding with the start of the action potential depolarization phase.

Relative refractory period

The relative refractory period is the second subphase of the refractory period and occurs immediately after the absolute refractory period. During this, a second action potential can be generated, however, its initiation requires a suprathreshold (stronger than normal) stimulus.

During the repolarization phase, the efflux of potassium ions can partly counteract the influx of sodium ions, necessitating a larger stimulus to activate greater numbers of voltage-gated sodium channels. During the hyperpolarization phase, the efflux of potassium ions leads to a shift in charge that moves the membrane potential further from the threshold, thereby making it more challenging for another action potential to occur. 

The relative refractory period is approximately half the duration of the absolute refractory period and together they last about 1-2 milliseconds in neurons.

Role of the refractory periods

The refractory period phenomenon plays several crucial roles in neuronal function:

  1. Securing forward propagation: The refractoriness of the already depolarized parts of the membrane ensures the unidirectional propagation of an impulse along the axon.
  2. Distinguishing action potentials from graded potentials: The refractory period serves as a distinguishing factor between action potentials and graded potentials. In graded potentials, two sequential stimuli applied in a certain area can be summed, potentially reaching the threshold potential at the axon hillock. However, during action potential transmission, regardless of the strength of a subsequent stimulus, no additional impulse can be generated.
  3. Preventing neuronal overstimulation: By allowing adequate time for resetting, the refractory period acts as a mechanism to prevent neuronal overstimulation.
  4. Regulating signal transmission frequency: The refractory period regulates the frequency of signal transmission. Specifically, the absolute refractory period preserves the bare minimum frequency, ensuring that neurons fire at an appropriate rate.

Refractory period and myelination

There is a notable disparity in the speed and frequency of signal transmission between myelinated and nonmyelinated nerve fibers. Myelinated nerve fibers exhibit an accelerated conduction rate compared to their nonmyelinated counterparts. Proportionally, the refractory period in myelinated axons is relatively shorter than in nonmyelinated axons. This decreased refractory period in myelinated nerve fibers correlates with an increased rate of impulse transmission.

Clinical relations

Local anesthetic agents exert their effects by reversibly binding to voltage-gated sodium channels, thereby obstructing their pores. Notably, they demonstrate a higher affinity for sodium channels in their inactivated states. Their affinity for sodium channels in the resting state is seventeen times lower than for those in the inactivated state. As neurons fire, their sodium channels increasingly transition to the inactivated state.

Consequently, the anesthetic drug more readily binds to and obstructs these channels, prolonging both the repolarization phase and subsequent channel reactivation. This extension of the total refractory period impedes the transmission of new impulses. Thus, until the effects of the local anesthetic subside and sodium channels revert to their resting conformation, the initiation of new action potentials remains inhibited.

This is the mechanism by which the transmission of pain signals are impeded during medical procedures such as surgeries.

Sources

All content published on Kenhub is reviewed by medical and anatomy experts. The information we provide is grounded on academic literature and peer-reviewed research. Kenhub does not provide medical advice. You can learn more about our content creation and review standards by reading our content quality guidelines.
  • Betts, J.G., Desaix, P., Johnson, E., Johnson, J.E., Korol, O., Kruse, D., Poe, B., Wise, J.A., Womble, M., Young., K.A. (2022). Anatomy and Physiology 2e. Retrieved from https://openstax.org/k12/anato...
  • Hall, J.E., Hall, M.E. (2021). Guyton and Hall Textbook of Medical Physiology. Philadelphia, PA: Elsevier.
  • Meechan, J.G. (2008). Local anaesthesia. Oral Surgery, 1, 3-5.
  • Silverthorn, D.E. (2018). Human Physiology, an Integrated Approach. London, England: Pearson.

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