Refractory period (physiology)

Last updated October 03, 2023

Refractoriness is the fundamental property of any object of autowave nature (especially excitable medium) not responding to stimuli, if the object stays in the specific refractory state. In common sense, refractory period is the characteristic recovery time, a period that is associated with the motion of the image point on the left branch of the isocline ${\dot {u}}=0$ ^{[B: 1]} (for more details, see also Reaction–diffusion and Parabolic partial differential equation).

In physiology,^{[B: 2]} a refractory period is a period of time during which an organ or cell is incapable of repeating a particular action, or (more precisely) the amount of time it takes for an excitable membrane to be ready for a second stimulus once it returns to its resting state following an excitation. It most commonly refers to electrically excitable muscle cells or neurons. Absolute refractory period corresponds to depolarization and repolarization, whereas relative refractory period corresponds to hyperpolarization.

Electrochemical usage

After initiation of an action potential, the refractory period is defined two ways: The absolute refractory period coincides with nearly the entire duration of the action potential. In neurons, it is caused by the inactivation of the Na⁺ channels that originally opened to depolarize the membrane. These channels remain inactivated until the membrane hyperpolarizes. The channels then close, de-inactivate, and regain their ability to open in response to stimulus.

The relative refractory period immediately follows the absolute. As voltage-gated potassium channels open to terminate the action potential by repolarizing the membrane, the potassium conductance of the membrane increases dramatically. K⁺ ions moving out of the cell bring the membrane potential closer to the equilibrium potential for potassium. This causes brief hyperpolarization of the membrane, that is, the membrane potential becomes transiently more negative than the normal resting potential. Until the potassium conductance returns to the resting value, a greater stimulus will be required to reach the initiation threshold for a second depolarization. The return to the equilibrium resting potential marks the end of the relative refractory period.

Cardiac refractory period

Effective Refractory Period ERP.svg — Effective Refractory Period

The refractory period in cardiac physiology is related to the ion currents that, in cardiac cells as in nerve cells, flow into and out of the cell freely. The flow of ions translates into a change in the voltage of the inside of the cell relative to the extracellular space. As in nerve cells, this characteristic change in voltage is referred to as an action potential. Unlike that in nerve cells, the cardiac action potential duration is closer to 100 ms (with variations depending on cell type, autonomic tone, etc.). After an action potential initiates, the cardiac cell is unable to initiate another action potential for some duration of time (which is slightly shorter than the "true" action potential duration). This period of time is referred to as the refractory period, which is 250ms in duration and helps to protect the heart.

In the classical sense, the cardiac refractory period is separated into an absolute refractory period and a relative refractory period. During the absolute refractory period, a new action potential cannot be elicited. During the relative refractory period, a new action potential can be elicited under the correct circumstances.

The cardiac refractory period can result in different forms of re-entry, which are a cause of tachycardia.^[1]^{[B: 3]} Vortices of excitation in the myocardium (autowave vortices) are a form of re-entry. Such vortices can be a mechanism of life-threatening cardiac arrhythmias. In particular, the autowave reverberator, more commonly referred to as spiral waves or rotors, can be found within the atria and may be a cause of atrial fibrillation.

Neuronal refractory period

The refractory period in a neuron occurs after an action potential and generally lasts one millisecond. An action potential consists of three phases.

Phase one is depolarization. During depolarization, voltage-gated sodium ion channels open, increasing the neuron's membrane conductance for sodium ions and depolarizing the cell's membrane potential (from typically -70 mV toward a positive potential). In other words, the membrane is made less negative. After the potential reaches the activation threshold (-55 mV), the depolarization is actively driven by the neuron and overshoots the equilibrium potential of an activated membrane (+30 mV).

Phase two is repolarization. During repolarization, voltage-gated sodium ion channels inactivate (different from the closed state) due to the now-depolarized membrane, and voltage-gated potassium channels activate (open). Both the inactivation of the sodium ion channels and the opening of the potassium ion channels act to repolarize the cell's membrane potential back to its resting membrane potential.

When the cell's membrane voltage overshoots its resting membrane potential (near -60 mV), the cell enters a phase of hyperpolarization. This is due to a larger-than-resting potassium conductance across the cell membrane. This potassium conductance eventually drops and the cell returns to its resting membrane potential.

Recent research has shown that neuronal refractory periods can exceed 20 milliseconds. Furthermore, the relation between hyperpolarization and the neuronal refractory was questioned, as neuronal refractory periods were observed for neurons that do not exhibit hyperpolarization.^[2]^[3] The neuronal refractory period was shown to be dependent on the origin of the input signal to the neuron, as well as the preceding spiking activity of the neuron.^[3]

The refractory periods are due to the inactivation property of voltage-gated sodium channels and the lag of potassium channels in closing. Voltage-gated sodium channels have two gating mechanisms, the activation mechanism that opens the channel with depolarization and the inactivation mechanism that closes the channel with repolarization. While the channel is in the inactive state, it will not open in response to depolarization. The period when the majority of sodium channels remain in the inactive state is the absolute refractory period. After this period, there are enough voltage-activated sodium channels in the closed (active) state to respond to depolarization. However, voltage-gated potassium channels that opened in response to repolarization do not close as quickly as voltage-gated sodium channels; to return to the active closed state. During this time, the extra potassium conductance means that the membrane is at a higher threshold and will require a greater stimulus to cause action potentials to fire. In other words, because the membrane potential inside the axon becomes increasingly negative relative to the outside of the membrane, a stronger stimulus will be required to reach the threshold voltage, and thus, initiate another action potential. This period is the relative refractory period.

Skeletal muscle refractory period

The muscle action potential lasts roughly 2–4 ms and the absolute refractory period is roughly 1–3 ms, shorter than other cells.

Related Research Articles

An action potential occurs when the membrane potential of a specific cell rapidly rises and falls. This depolarization then causes adjacent locations to similarly depolarize. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and in some plant cells. Certain endocrine cells such as pancreatic beta cells, and certain cells of the anterior pituitary gland are also excitable cells.

<span class="mw-page-title-main">Cardiac pacemaker</span> Network of cells that facilitate rhythmic heart contraction

The contraction of cardiac muscle in all animals is initiated by electrical impulses known as action potentials that in the heart are known as cardiac action potentials. The rate at which these impulses fire controls the rate of cardiac contraction, that is, the heart rate. The cells that create these rhythmic impulses, setting the pace for blood pumping, are called pacemaker cells, and they directly control the heart rate. They make up the cardiac pacemaker, that is, the natural pacemaker of the heart. In most humans, the highest concentration of pacemaker cells is in the sinoatrial (SA) node, the natural and primary pacemaker, and the resultant rhythm is a sinus rhythm.

In electrocardiography, the ventricular cardiomyocyte membrane potential is about −90 mV at rest, which is close to the potassium reversal potential. When an action potential is generated, the membrane potential rises above this level in four distinct phases.

Hyperpolarization is a change in a cell's membrane potential that makes it more negative. It is the opposite of a depolarization. It inhibits action potentials by increasing the stimulus required to move the membrane potential to the action potential threshold.

In biology, depolarization or hypopolarization is a change within a cell, during which the cell undergoes a shift in electric charge distribution, resulting in less negative charge inside the cell compared to the outside. Depolarization is essential to the function of many cells, communication between cells, and the overall physiology of an organism.

Membrane potential is the difference in electric potential between the interior and the exterior of a biological cell. That is, there is a difference in the energy required for electric charges to move from the internal to exterior cellular environments and vice versa, as long as there is no acquisition of kinetic energy or the production of radiation. The concentration gradients of the charges directly determine this energy requirement. For the exterior of the cell, typical values of membrane potential, normally given in units of milli volts and denoted as mV, range from –80 mV to –40 mV.

Graded potentials are changes in membrane potential that vary in size, as opposed to being all-or-none. They include diverse potentials such as receptor potentials, electrotonic potentials, subthreshold membrane potential oscillations, slow-wave potential, pacemaker potentials, and synaptic potentials, which scale with the magnitude of the stimulus. They arise from the summation of the individual actions of ligand-gated ion channel proteins, and decrease over time and space. They do not typically involve voltage-gated sodium and potassium channels. These impulses are incremental and may be excitatory or inhibitory. They occur at the postsynaptic dendrite in response to presynaptic neuron firing and release of neurotransmitter, or may occur in skeletal, smooth, or cardiac muscle in response to nerve input. The magnitude of a graded potential is determined by the strength of the stimulus.

In electrophysiology, the threshold potential is the critical level to which a membrane potential must be depolarized to initiate an action potential. In neuroscience, threshold potentials are necessary to regulate and propagate signaling in both the central nervous system (CNS) and the peripheral nervous system (PNS).

The cardiac action potential is a brief change in voltage across the cell membrane of heart cells. This is caused by the movement of charged atoms between the inside and outside of the cell, through proteins called ion channels. The cardiac action potential differs from action potentials found in other types of electrically excitable cells, such as nerves. Action potentials also vary within the heart; this is due to the presence of different ion channels in different cells.

End plate potentials (EPPs) are the voltages which cause depolarization of skeletal muscle fibers caused by neurotransmitters binding to the postsynaptic membrane in the neuromuscular junction. They are called "end plates" because the postsynaptic terminals of muscle fibers have a large, saucer-like appearance. When an action potential reaches the axon terminal of a motor neuron, vesicles carrying neurotransmitters are exocytosed and the contents are released into the neuromuscular junction. These neurotransmitters bind to receptors on the postsynaptic membrane and lead to its depolarization. In the absence of an action potential, acetylcholine vesicles spontaneously leak into the neuromuscular junction and cause very small depolarizations in the postsynaptic membrane. This small response (~0.4mV) is called a miniature end plate potential (MEPP) and is generated by one acetylcholine-containing vesicle. It represents the smallest possible depolarization which can be induced in a muscle.

<span class="mw-page-title-main">Repolarization</span>

In neuroscience, repolarization refers to the change in membrane potential that returns it to a negative value just after the depolarization phase of an action potential which has changed the membrane potential to a positive value. The repolarization phase usually returns the membrane potential back to the resting membrane potential. The efflux of potassium (K⁺) ions results in the falling phase of an action potential. The ions pass through the selectivity filter of the K⁺ channel pore.

Voltage-gated ion channels are a class of transmembrane proteins that form ion channels that are activated by changes in the electrical membrane potential near the channel. The membrane potential alters the conformation of the channel proteins, regulating their opening and closing. Cell membranes are generally impermeable to ions, thus they must diffuse through the membrane through transmembrane protein channels. They have a crucial role in excitable cells such as neuronal and muscle tissues, allowing a rapid and co-ordinated depolarization in response to triggering voltage change. Found along the axon and at the synapse, voltage-gated ion channels directionally propagate electrical signals. Voltage-gated ion-channels are usually ion-specific, and channels specific to sodium (Na⁺), potassium (K⁺), calcium (Ca²⁺), and chloride (Cl⁻) ions have been identified. The opening and closing of the channels are triggered by changing ion concentration, and hence charge gradient, between the sides of the cell membrane.

Molecular neuroscience is a branch of neuroscience that observes concepts in molecular biology applied to the nervous systems of animals. The scope of this subject covers topics such as molecular neuroanatomy, mechanisms of molecular signaling in the nervous system, the effects of genetics and epigenetics on neuronal development, and the molecular basis for neuroplasticity and neurodegenerative diseases. As with molecular biology, molecular neuroscience is a relatively new field that is considerably dynamic.

In neuroscience, the axolemma is the cell membrane of an axon, the branch of a neuron through which signals are transmitted. The axolemma is a three-layered, bilipid membrane. Under standard electron microscope preparations, the structure is approximately 8 nanometers thick.

Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na⁺) through a cell's membrane. They belong to the superfamily of cation channels.

Low-threshold spikes (LTS) refer to membrane depolarizations by the T-type calcium channel. LTS occur at low, negative, membrane depolarizations. They often follow a membrane hyperpolarization, which can be the result of decreased excitability or increased inhibition. LTS result in the neuron reaching the threshold for an action potential. LTS is a large depolarization due to an increase in Ca²⁺ conductance, so LTS is mediated by calcium (Ca²⁺) conductance. The spike is typically crowned by a burst of two to seven action potentials, which is known as a low-threshold burst. LTS are voltage dependent and are inactivated if the cell's resting membrane potential is more depolarized than −60mV. LTS are deinactivated, or recover from inactivation, if the cell is hyperpolarized and can be activated by depolarizing inputs, such as excitatory postsynaptic potentials (EPSP). LTS were discovered by Rodolfo Llinás and coworkers in the 1980s.

Cellular neuroscience is a branch of neuroscience concerned with the study of neurons at a cellular level. This includes morphology and physiological properties of single neurons. Several techniques such as intracellular recording, patch-clamp, and voltage-clamp technique, pharmacology, confocal imaging, molecular biology, two photon laser scanning microscopy and Ca²⁺ imaging have been used to study activity at the cellular level. Cellular neuroscience examines the various types of neurons, the functions of different neurons, the influence of neurons upon each other, and how neurons work together.

Nonsynaptic plasticity is a form of neuroplasticity that involves modification of ion channel function in the axon, dendrites, and cell body that results in specific changes in the integration of excitatory postsynaptic potentials and inhibitory postsynaptic potentials. Nonsynaptic plasticity is a modification of the intrinsic excitability of the neuron. It interacts with synaptic plasticity, but it is considered a separate entity from synaptic plasticity. Intrinsic modification of the electrical properties of neurons plays a role in many aspects of plasticity from homeostatic plasticity to learning and memory itself. Nonsynaptic plasticity affects synaptic integration, subthreshold propagation, spike generation, and other fundamental mechanisms of neurons at the cellular level. These individual neuronal alterations can result in changes in higher brain function, especially learning and memory. However, as an emerging field in neuroscience, much of the knowledge about nonsynaptic plasticity is uncertain and still requires further investigation to better define its role in brain function and behavior.

In electrophysiology, the term gating refers to the opening (activation) or closing of ion channels. This change in conformation is a response to changes in transmembrane voltage.

A depolarizing prepulse (DPP) is an electrical stimulus that causes the potential difference measured across a neuronal membrane to become more positive or less negative, and precedes another electrical stimulus. DPPs may be of either the voltage or current stimulus variety and have been used to inhibit neural activity, selectively excite neurons, and increase the pain threshold associated with electrocutaneous stimulation.

References

Books

↑ Грехова, М. Т., ed. (1981). Автоволновые процессы в системах с диффузией[Autowave processes in systems with diffusion] (in Russian). Горький: Институт прикладной математики АН СССР. p. 287.
↑ Schmidt, Robert F.; Thews, Gerhard (1983). Human physiology. Springer-Verlag. p. 725. ISBN 978-3540116691.
↑ Елькин, Ю.Е.; Москаленко, А.В. (2009). "Базовые механизмы аритмий сердца" [Basic mechanisms of cardiac arrhythmias]. In Ardashev, prof. A.V. (ed.). Клиническая аритмология [Clinical arrhythmology] (in Russian). Moscow: MedPraktika. p. 1220. ISBN 978-5-98803-198-7.

↑ Wiener, N.; Rosenblueth, A. (July 1946). "The mathematical formulation of the problem of conduction of impulses in a network of connected excitable elements, specifically in cardiac muscle". Archivos del Instituto de Cardiologia de Mexico. 16 (3): 205–265. ISSN 0020-3785. PMID 20245817.
↑ Sardi, Shira; Vardi, Roni; Tugendhaft, Yael; Sheinin, Anton; Goldental, Amir; Kanter, Ido (2022-01-03). "Long anisotropic absolute refractory periods with rapid rise times to reliable responsiveness". Physical Review E. 105 (1): 014401. arXiv: 2111.02689 . doi:10.1103/PhysRevE.105.014401. PMID 35193251. S2CID 242757511.
1 2 Vardi, Roni; Tugendhaft, Yael; Sardi, Shira; Kanter, Ido (2021-06-01). "Significant anisotropic neuronal refractory period plasticity". EPL (Europhysics Letters). 134 (6): 60007. arXiv: 2109.02041 . doi:10.1209/0295-5075/ac177a. ISSN 0295-5075. S2CID 237408101.

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[b-Gorky-1981-1] Грехова, М. Т., ed. (1981). Автоволновые процессы в системах с диффузией[Autowave processes in systems with diffusion] (in Russian). Горький: Институт прикладной математики АН СССР. p. 287.

[b-Schmidt-1983-2] Schmidt, Robert F.; Thews, Gerhard (1983). Human physiology. Springer-Verlag. p. 725. ISBN 978-3540116691.

[b-Ardashev-2009p06-4] Елькин, Ю.Е.; Москаленко, А.В. (2009). "Базовые механизмы аритмий сердца" [Basic mechanisms of cardiac arrhythmias]. In Ardashev, prof. A.V. (ed.). Клиническая аритмология [Clinical arrhythmology] (in Russian). Moscow: MedPraktika. p. 1220. ISBN 978-5-98803-198-7.

[3] Wiener, N.; Rosenblueth, A. (July 1946). "The mathematical formulation of the problem of conduction of impulses in a network of connected excitable elements, specifically in cardiac muscle". Archivos del Instituto de Cardiologia de Mexico. 16 (3): 205–265. ISSN 0020-3785. PMID 20245817.

[5] Sardi, Shira; Vardi, Roni; Tugendhaft, Yael; Sheinin, Anton; Goldental, Amir; Kanter, Ido (2022-01-03). "Long anisotropic absolute refractory periods with rapid rise times to reliable responsiveness". Physical Review E. 105 (1): 014401. arXiv: 2111.02689 . doi:10.1103/PhysRevE.105.014401. PMID 35193251. S2CID 242757511.

[:0-6] 1 2 Vardi, Roni; Tugendhaft, Yael; Sardi, Shira; Kanter, Ido (2021-06-01). "Significant anisotropic neuronal refractory period plasticity". EPL (Europhysics Letters). 134 (6): 60007. arXiv: 2109.02041 . doi:10.1209/0295-5075/ac177a. ISSN 0295-5075. S2CID 237408101.

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