Weakness is a symptom of many different medical conditions. The causes are many and can be divided into conditions that have true or perceived muscle weakness. True muscle weakness is a primary symptom of a variety of skeletal muscle diseases, including muscular dystrophy and inflammatory myopathy . It occurs in neuromuscular junction disorders, such as myasthenia gravis .
119-407: Muscle cells work by detecting a flow of electrical impulses from the brain , which signals them to contract through the release of calcium by the sarcoplasmic reticulum . Fatigue (reduced ability to generate force) may occur due to the nerve, or within the muscle cells themselves. New research from scientists at Columbia University suggests that muscle fatigue is caused by calcium leaking out of
238-436: A high-frequency signal . After an extended period of maximum contraction, the nerve's signal reduces in frequency and the force generated by the contraction diminishes. There is no sensation of pain or discomfort, the muscle appears to simply 'stop listening' and gradually cease to move, often lengthening . As there is insufficient stress on the muscles and tendons, there will often be no delayed onset muscle soreness following
357-426: A pseudoathletic appearance , exercise intolerance , myalgia (muscle pain), fasciculations (muscle twitches), myotonia (delayed muscle relaxation), hypotonia (lack of resistance to passive movement), fixed muscle weakness (a static symptom ), or premature muscle fatigue (a dynamic symptom ). Neuromuscular disease can be caused by autoimmune disorders, genetic/hereditary disorders and some forms of
476-506: A cell are determined by the structure of its membrane. A cell membrane consists of a lipid bilayer of molecules in which larger protein molecules are embedded. The lipid bilayer is highly resistant to movement of electrically charged ions, so it functions as an insulator. The large membrane-embedded proteins, in contrast, provide channels through which ions can pass across the membrane. Action potentials are driven by channel proteins whose configuration switches between closed and open states as
595-430: A current impulse is a function of the membrane input resistance . As a cell grows, more channels are added to the membrane, causing a decrease in input resistance. A mature neuron also undergoes shorter changes in membrane potential in response to synaptic currents. Neurons from a ferret lateral geniculate nucleus have a longer time constant and larger voltage deflection at P0 than they do at P30. One consequence of
714-646: A few types of action potentials, such as the cardiac action potential and the action potential in the single-cell alga Acetabularia , respectively. Although action potentials are generated locally on patches of excitable membrane, the resulting currents can trigger action potentials on neighboring stretches of membrane, precipitating a domino-like propagation. In contrast to passive spread of electric potentials ( electrotonic potential ), action potentials are generated anew along excitable stretches of membrane and propagate without decay. Myelinated sections of axons are not excitable and do not produce action potentials and
833-441: A force far below what a muscle could potentially generate, and barring pathology , neuromuscular fatigue is seldom an issue. For extremely powerful contractions that are close to the upper limit of a muscle's ability to generate force, neuromuscular fatigue can become a limiting factor in untrained individuals. In novice strength trainers , the muscle's ability to generate force is most strongly limited by nerve's ability to sustain
952-450: A function of the voltage difference between the interior and exterior of the cell. These voltage-sensitive proteins are known as voltage-gated ion channels . All cells in animal body tissues are electrically polarized – in other words, they maintain a voltage difference across the cell's plasma membrane , known as the membrane potential . This electrical polarization results from a complex interplay between protein structures embedded in
1071-467: A further rise in the membrane potential. An action potential occurs when this positive feedback cycle ( Hodgkin cycle ) proceeds explosively. The time and amplitude trajectory of the action potential are determined by the biophysical properties of the voltage-gated ion channels that produce it. Several types of channels capable of producing the positive feedback necessary to generate an action potential do exist. Voltage-gated sodium channels are responsible for
1190-494: A given cell. (Exceptions are discussed later in the article). In most neurons, the entire process takes place in about a thousandth of a second. Many types of neurons emit action potentials constantly at rates of up to 10–100 per second. However, some types are much quieter, and may go for minutes or longer without emitting any action potentials. Action potentials result from the presence in a cell's membrane of special types of voltage-gated ion channels . A voltage-gated ion channel
1309-491: A lack of intracellular energy sources to fuel contractions. In essence, the muscle stops contracting because it lacks the energy to do so. In some conditions, such as myasthenia gravis , muscle strength is normal when resting, but true weakness occurs after the muscle has been subjected to exercise. This is also true for some cases of Myalgic encephalomyelitis/chronic fatigue syndrome , where objective post-exertion muscle weakness with delayed recovery time has been measured and
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#17328905052001428-417: A large group of diseases, many of them hereditary or resulting from genetic mutations , where the muscle integrity is disrupted, they lead to progressive loss of strength and decreased life span. Further causes of neuromuscular diseases are: Inflammatory muscle disorders Tumors Diagnostic procedures that may reveal muscular disorders include direct clinical observations. This usually starts with
1547-418: A local, muscle-specific inability to do work. Neuromuscular fatigue can be either central or peripheral. The central fatigue is generally described in terms of a reduction in the neural drive or nerve-based motor command to working muscles that results in a decline in the force output. It has been suggested that the reduced neural drive during exercise may be a protective mechanism to prevent organ failure if
1666-449: A metabolic byproduct. Contrary to common belief, lactic acid accumulation doesn't actually cause the burning sensation felt when people exhaust their oxygen and oxidative metabolism, but in actuality, lactic acid in presence of oxygen recycles to produce pyruvate in the liver, which is known as the Cori cycle . Substrates produce metabolic fatigue by being depleted during exercise, resulting in
1785-413: A minimum diameter (roughly 1 micrometre ), myelination increases the conduction velocity of an action potential, typically tenfold. Conversely, for a given conduction velocity, myelinated fibers are smaller than their unmyelinated counterparts. For example, action potentials move at roughly the same speed (25 m/s) in a myelinated frog axon and an unmyelinated squid giant axon , but the frog axon has
1904-402: A neuron has a negative charge, relative to the cell exterior, from the movement of K out of the cell. The neuron membrane is more permeable to K than to other ions, allowing this ion to selectively move out of the cell, down its concentration gradient. This concentration gradient along with potassium leak channels present on the membrane of the neuron causes an efflux of potassium ions making
2023-410: A presynaptic neuron. Typically, neurotransmitter molecules are released by the presynaptic neuron . These neurotransmitters then bind to receptors on the postsynaptic cell. This binding opens various types of ion channels . This opening has the further effect of changing the local permeability of the cell membrane and, thus, the membrane potential. If the binding increases the voltage (depolarizes
2142-413: A roughly 30-fold smaller diameter and 1000-fold smaller cross-sectional area. Also, since the ionic currents are confined to the nodes of Ranvier, far fewer ions "leak" across the membrane, saving metabolic energy. This saving is a significant selective advantage , since the human nervous system uses approximately 20% of the body's metabolic energy. The length of axons' myelinated segments is important to
2261-412: A single soma , a single axon and one or more axon terminals . Dendrites are cellular projections whose primary function is to receive synaptic signals. Their protrusions, known as dendritic spines , are designed to capture the neurotransmitters released by the presynaptic neuron. They have a high concentration of ligand-gated ion channels . These spines have a thin neck connecting a bulbous protrusion to
2380-455: Is a feature of some of the published definitions. Asthenia or asthaenia ( Greek : ἀσθένεια , literally lack of strength but also disease ) is a medical term referring to a condition in which the body lacks or has lost strength either as a whole or in any of its parts. It is a poorly defined condition that can include true or primary muscle weakness or perceived muscle weakness. For perceived muscle weakness, asthenia has been described as
2499-620: Is a lack of muscle strength. The causes are many and can be divided into conditions that have either true or perceived muscle weakness. True muscle weakness is a primary symptom of a variety of skeletal muscle diseases, including muscular dystrophy and inflammatory myopathy. It occurs in neuromuscular diseases , such as myasthenia gravis. Perceived muscle weakness occurs in diseases such as sleep disorders, and depression. Muscle fatigue can be central, neuromuscular, or peripheral muscular. Central muscle fatigue manifests as an overall sense of energy deprivation, and peripheral muscle weakness manifests as
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#17328905052002618-407: Is a source of energy. The fundamental difference between the peripheral and central theories of muscle fatigue is that the peripheral model of muscle fatigue assumes failure at one or more sites in the chain that initiates muscle contraction. Peripheral regulation therefore depends on the localized metabolic chemical conditions of the local muscle affected, whereas the central model of muscle fatigue
2737-406: Is a transmembrane protein that has three key properties: Thus, a voltage-gated ion channel tends to be open for some values of the membrane potential, and closed for others. In most cases, however, the relationship between membrane potential and channel state is probabilistic and involves a time delay. Ion channels switch between conformations at unpredictable times: The membrane potential determines
2856-547: Is also a side effect of some medications and treatments, such as Ritonavir (a protease inhibitor used in HIV treatment). Differentiating psychogenic (perceived) asthenia and true asthenia from myasthenia is often difficult, and in time apparent psychogenic asthenia accompanying many chronic disorders is seen to progress into a primary weakness. Myasthenia or myasthaenia (my- from Greek : μυο meaning "muscle" + -asthenia [ ἀσθένεια ] meaning "weakness"), or simply muscle weakness,
2975-411: Is an integrated mechanism that works to preserve the integrity of the system by initiating muscle fatigue through muscle derecruitment, based on collective feedback from the periphery, before cellular or organ failure occurs. Therefore, the feedback that is read by this central regulator could include chemical and mechanical as well as cognitive cues. The significance of each of these factors will depend on
3094-462: Is called the relative refractory period . The positive feedback of the rising phase slows and comes to a halt as the sodium ion channels become maximally open. At the peak of the action potential, the sodium permeability is maximized and the membrane voltage V m is nearly equal to the sodium equilibrium voltage E Na . However, the same raised voltage that opened the sodium channels initially also slowly shuts them off, by closing their pores;
3213-467: Is coupled with the opening and closing of ion channels , which in turn alter the ionic permeabilities of the membrane and its voltage. These voltage changes can again be excitatory (depolarizing) or inhibitory (hyperpolarizing) and, in some sensory neurons, their combined effects can depolarize the axon hillock enough to provoke action potentials. Some examples in humans include the olfactory receptor neuron and Meissner's corpuscle , which are critical for
3332-446: Is increased, sodium ion channels open, allowing the entry of sodium ions into the cell. This is followed by the opening of potassium ion channels that permit the exit of potassium ions from the cell. The inward flow of sodium ions increases the concentration of positively charged cations in the cell and causes depolarization, where the potential of the cell is higher than the cell's resting potential . The sodium channels close at
3451-415: Is often said to "fire". Action potentials are generated by special types of voltage-gated ion channels embedded in a cell's plasma membrane . These channels are shut when the membrane potential is near the (negative) resting potential of the cell, but they rapidly begin to open if the membrane potential increases to a precisely defined threshold voltage, depolarising the transmembrane potential. When
3570-556: Is prevented. Even the electrical activity of the cell itself may play a role in channel expression. If action potentials in Xenopus myocytes are blocked, the typical increase in sodium and potassium current density is prevented or delayed. This maturation of electrical properties is seen across species. Xenopus sodium and potassium currents increase drastically after a neuron goes through its final phase of mitosis . The sodium current density of rat cortical neurons increases by 600% within
3689-465: Is to activate intracellular processes. In muscle cells, for example, an action potential is the first step in the chain of events leading to contraction. In beta cells of the pancreas , they provoke release of insulin . Action potentials in neurons are also known as " nerve impulses " or " spikes ", and the temporal sequence of action potentials generated by a neuron is called its " spike train ". A neuron that emits an action potential, or nerve impulse,
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3808-409: Is to boost the signal in order to prevent significant signal decay. At the furthest end, the axon loses its insulation and begins to branch into several axon terminals . These presynaptic terminals, or synaptic boutons, are a specialized area within the axon of the presynaptic cell that contains neurotransmitters enclosed in small membrane-bound spheres called synaptic vesicles . Before considering
3927-401: Is transiently unusually low, making the membrane voltage V m even closer to the potassium equilibrium voltage E K . The membrane potential goes below the resting membrane potential. Hence, there is an undershoot or hyperpolarization , termed an afterhyperpolarization , that persists until the membrane potassium permeability returns to its usual value, restoring the membrane potential to
4046-409: Is −70 mV. This means that the interior of the cell has a negative voltage relative to the exterior. In most types of cells, the membrane potential usually stays fairly constant. Some types of cells, however, are electrically active in the sense that their voltages fluctuate over time. In some types of electrically active cells, including neurons and muscle cells, the voltage fluctuations frequently take
4165-505: The Nobel Prize in Physiology or Medicine in 1963. However, their model considers only two types of voltage-sensitive ion channels, and makes several assumptions about them, e.g., that their internal gates open and close independently of one another. In reality, there are many types of ion channels, and they do not always open and close independently. A typical action potential begins at
4284-454: The activated state is very low: A channel in the inactivated state is refractory until it has transitioned back to the deactivated state. The outcome of all this is that the kinetics of the Na V channels are governed by a transition matrix whose rates are voltage-dependent in a complicated way. Since these channels themselves play a major role in determining the voltage, the global dynamics of
4403-456: The anterior pituitary gland are also excitable cells. In neurons, action potentials play a central role in cell–cell communication by providing for—or with regard to saltatory conduction , assisting—the propagation of signals along the neuron's axon toward synaptic boutons situated at the ends of an axon; these signals can then connect with other neurons at synapses, or to motor cells or glands. In other types of cells, their main function
4522-413: The axon hillock with a sufficiently strong depolarization, e.g., a stimulus that increases V m . This depolarization is often caused by the injection of extra sodium cations into the cell; these cations can come from a wide variety of sources, such as chemical synapses , sensory neurons or pacemaker potentials . For a neuron at rest, there is a high concentration of sodium and chloride ions in
4641-437: The central nervous system . Myelin sheath reduces membrane capacitance and increases membrane resistance in the inter-node intervals, thus allowing a fast, saltatory movement of action potentials from node to node. Myelination is found mainly in vertebrates , but an analogous system has been discovered in a few invertebrates, such as some species of shrimp . Not all neurons in vertebrates are myelinated; for example, axons of
4760-420: The extracellular fluid compared to the intracellular fluid , while there is a high concentration of potassium ions in the intracellular fluid compared to the extracellular fluid. The difference in concentrations, which causes ions to move from a high to a low concentration , and electrostatic effects (attraction of opposite charges) are responsible for the movement of ions in and out of the neuron. The inside of
4879-507: The heart provide a good example. Although such pacemaker potentials have a natural rhythm , it can be adjusted by external stimuli; for instance, heart rate can be altered by pharmaceuticals as well as signals from the sympathetic and parasympathetic nerves. The external stimuli do not cause the cell's repetitive firing, but merely alter its timing. In some cases, the regulation of frequency can be more complex, leading to patterns of action potentials, such as bursting . The course of
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4998-461: The inward current becomes primarily carried by sodium channels. Second, the delayed rectifier , a potassium channel current, increases to 3.5 times its initial strength. In order for the transition from a calcium-dependent action potential to a sodium-dependent action potential to proceed new channels must be added to the membrane. If Xenopus neurons are grown in an environment with RNA synthesis or protein synthesis inhibitors that transition
5117-406: The optic nerve . In sensory neurons, action potentials result from an external stimulus. However, some excitable cells require no such stimulus to fire: They spontaneously depolarize their axon hillock and fire action potentials at a regular rate, like an internal clock. The voltage traces of such cells are known as pacemaker potentials . The cardiac pacemaker cells of the sinoatrial node in
5236-692: The synaptic cleft . In addition, backpropagating action potentials have been recorded in the dendrites of pyramidal neurons , which are ubiquitous in the neocortex. These are thought to have a role in spike-timing-dependent plasticity . In the Hodgkin–Huxley membrane capacitance model , the speed of transmission of an action potential was undefined and it was assumed that adjacent areas became depolarized due to released ion interference with neighbouring channels. Measurements of ion diffusion and radii have since shown this not to be possible. Moreover, contradictory measurements of entropy changes and timing disputed
5355-486: The 'ratchetting' that results in contraction according to the sliding filament model . Creatine phosphate stores energy so ATP can be rapidly regenerated within the muscle cells from adenosine diphosphate (ADP) and inorganic phosphate ions, allowing for sustained powerful contractions that last between 5–7 seconds. Glycogen is the intramuscular storage form of glucose , used to generate energy quickly once intramuscular creatine stores are exhausted, producing lactic acid as
5474-524: The Na channels have not recovered from the inactivated state. The period during which no new action potential can be fired is called the absolute refractory period . At longer times, after some but not all of the ion channels have recovered, the axon can be stimulated to produce another action potential, but with a higher threshold, requiring a much stronger depolarization, e.g., to −30 mV. The period during which action potentials are unusually difficult to evoke
5593-518: The ability of Ca to stimulate actin and myosin to contract. Action potential 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 excitable cells , which include animal cells like neurons and muscle cells , as well as some plant cells . Certain endocrine cells such as pancreatic beta cells , and certain cells of
5712-427: The action potential can be divided into five parts: the rising phase, the peak phase, the falling phase, the undershoot phase, and the refractory period. During the rising phase the membrane potential depolarizes (becomes more positive). The point at which depolarization stops is called the peak phase. At this stage, the membrane potential reaches a maximum. Subsequent to this, there is a falling phase. During this stage
5831-411: The action potential moves in only one direction along an axon. The currents flowing in due to an action potential spread out in both directions along the axon. However, only the unfired part of the axon can respond with an action potential; the part that has just fired is unresponsive until the action potential is safely out of range and cannot restimulate that part. In the usual orthodromic conduction ,
5950-416: The action potential propagates from the axon hillock towards the synaptic knobs (the axonal termini); propagation in the opposite direction—known as antidromic conduction —is very rare. However, if a laboratory axon is stimulated in its middle, both halves of the axon are "fresh", i.e., unfired; then two action potentials will be generated, one traveling towards the axon hillock and the other traveling towards
6069-407: The action potentials, he showed that an action potential arriving on one side of the block could provoke another action potential on the other, provided that the blocked segment was sufficiently short. Once an action potential has occurred at a patch of membrane, the membrane patch needs time to recover before it can fire again. At the molecular level, this absolute refractory period corresponds to
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#17328905052006188-520: The axon hillock is the axon. This is a thin tubular protrusion traveling away from the soma. The axon is insulated by a myelin sheath. Myelin is composed of either Schwann cells (in the peripheral nervous system) or oligodendrocytes (in the central nervous system), both of which are types of glial cells . Although glial cells are not involved with the transmission of electrical signals, they communicate and provide important biochemical support to neurons. To be specific, myelin wraps multiple times around
6307-461: The axon hillock propagates as a wave along the axon. The currents flowing inwards at a point on the axon during an action potential spread out along the axon, and depolarize the adjacent sections of its membrane. If sufficiently strong, this depolarization provokes a similar action potential at the neighboring membrane patches. This basic mechanism was demonstrated by Alan Lloyd Hodgkin in 1937. After crushing or cooling nerve segments and thus blocking
6426-473: The axonal segment, forming a thick fatty layer that prevents ions from entering or escaping the axon. This insulation prevents significant signal decay as well as ensuring faster signal speed. This insulation, however, has the restriction that no channels can be present on the surface of the axon. There are, therefore, regularly spaced patches of membrane, which have no insulation. These nodes of Ranvier can be considered to be "mini axon hillocks", as their purpose
6545-520: The binding of the neurotransmitter. Some fraction of an excitatory voltage may reach the axon hillock and may (in rare cases) depolarize the membrane enough to provoke a new action potential. More typically, the excitatory potentials from several synapses must work together at nearly the same time to provoke a new action potential. Their joint efforts can be thwarted, however, by the counteracting inhibitory postsynaptic potentials . Neurotransmission can also occur through electrical synapses . Due to
6664-433: The biophysics of the action potential, but can more conveniently be referred to as Na V channels. (The "V" stands for "voltage".) An Na V channel has three possible states, known as deactivated , activated , and inactivated . The channel is permeable only to sodium ions when it is in the activated state. When the membrane potential is low, the channel spends most of its time in the deactivated (closed) state. If
6783-408: The capacitance model as acting alone. Alternatively, Gilbert Ling's adsorption hypothesis, posits that the membrane potential and action potential of a living cell is due to the adsorption of mobile ions onto adsorption sites of cells. A neuron 's ability to generate and propagate an action potential changes during development . How much the membrane potential of a neuron changes as the result of
6902-424: The cell, and a higher value called the threshold potential . At the axon hillock of a typical neuron, the resting potential is around –70 millivolts (mV) and the threshold potential is around –55 mV. Synaptic inputs to a neuron cause the membrane to depolarize or hyperpolarize ; that is, they cause the membrane potential to rise or fall. Action potentials are triggered when enough depolarization accumulates to bring
7021-422: The channel will eventually transition back to the deactivated state. During an action potential, most channels of this type go through a cycle deactivated → activated → inactivated → deactivated . This is only the population average behavior, however – an individual channel can in principle make any transition at any time. However, the likelihood of a channel's transitioning from the inactivated state directly to
7140-412: The channels open, they allow an inward flow of sodium ions, which changes the electrochemical gradient, which in turn produces a further rise in the membrane potential towards zero. This then causes more channels to open, producing a greater electric current across the cell membrane and so on. The process proceeds explosively until all of the available ion channels are open, resulting in a large upswing in
7259-795: The collagen disorder Ehlers–Danlos syndrome , exposure to environmental chemicals and poisoning which includes heavy metal poisoning . The failure of the electrical insulation surrounding nerves, the myelin , is seen in certain deficiency diseases, such as the failure of the body's system for absorbing vitamin B-12 . Diseases of the motor end plate include myasthenia gravis , a form of muscle weakness due to antibodies against acetylcholine receptor, and its related condition Lambert–Eaton myasthenic syndrome (LEMS). Tetanus and botulism are bacterial infections in which bacterial toxins cause increased or decreased muscle tone, respectively. Muscular dystrophies , including Duchenne's and Becker's , are
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#17328905052007378-988: The conduction velocity of action potentials. The most well-known of these is multiple sclerosis , in which the breakdown of myelin impairs coordinated movement. Neuromuscular disease A neuromuscular disease is any disease affecting the peripheral nervous system (PNS), the neuromuscular junctions , or skeletal muscles , all of which are components of the motor unit . Damage to any of these structures can cause muscle atrophy and weakness. Issues with sensation can also occur. Neuromuscular diseases can be acquired or genetic . Mutations of more than 650 genes have shown to be causes of neuromuscular diseases. Other causes include nerve or muscle degeneration , autoimmunity , toxins , medications , malnutrition , metabolic derangements , hormone imbalances , infection , nerve compression/entrapment , comprised blood supply , and trauma . Symptoms of neuromuscular disease may include numbness , paresthesia , muscle atrophy ,
7497-533: The course of an action potential are typically significantly larger than the initial stimulating current. Thus, the amplitude, duration, and shape of the action potential are determined largely by the properties of the excitable membrane and not the amplitude or duration of the stimulus. This all-or-nothing property of the action potential sets it apart from graded potentials such as receptor potentials , electrotonic potentials , subthreshold membrane potential oscillations , and synaptic potentials , which scale with
7616-490: The decreasing action potential duration is that the fidelity of the signal can be preserved in response to high frequency stimulation. Immature neurons are more prone to synaptic depression than potentiation after high frequency stimulation. In the early development of many organisms, the action potential is actually initially carried by calcium current rather than sodium current . The opening and closing kinetics of calcium channels during development are slower than those of
7735-436: The dendrite. This ensures that changes occurring inside the spine are less likely to affect the neighboring spines. The dendritic spine can, with rare exception (see LTP ), act as an independent unit. The dendrites extend from the soma, which houses the nucleus , and many of the "normal" eukaryotic organelles. Unlike the spines, the surface of the soma is populated by voltage activated ion channels. These channels help transmit
7854-431: The direct connection between excitable cells in the form of gap junctions , an action potential can be transmitted directly from one cell to the next in either direction. The free flow of ions between cells enables rapid non-chemical-mediated transmission. Rectifying channels ensure that action potentials move only in one direction through an electrical synapse. Electrical synapses are found in all nervous systems, including
7973-471: The driving force for a long burst of rapidly emitted sodium spikes. In cardiac muscle cells , on the other hand, an initial fast sodium spike provides a "primer" to provoke the rapid onset of a calcium spike, which then produces muscle contraction. Nearly all cell membranes in animals, plants and fungi maintain a voltage difference between the exterior and interior of the cell, called the membrane potential . A typical voltage across an animal cell membrane
8092-456: The duration of the relative refractory period is highly variable. The absolute refractory period is largely responsible for the unidirectional propagation of action potentials along axons. At any given moment, the patch of axon behind the actively spiking part is refractory, but the patch in front, not having been activated recently, is capable of being stimulated by the depolarization from the action potential. The action potential generated at
8211-541: The electrochemical gradient to the resting state. After an action potential has occurred, there is a transient negative shift, called the afterhyperpolarization . In animal cells, there are two primary types of action potentials. One type is generated by voltage-gated sodium channels , the other by voltage-gated calcium channels . Sodium-based action potentials usually last for under one millisecond, but calcium-based action potentials may last for 100 milliseconds or longer. In some types of neurons, slow calcium spikes provide
8330-438: The eventual reduction or lack of ability of a single muscle or local group of muscles to do work. The insufficiency of energy, i.e. sub-optimal aerobic metabolism , generally results in the accumulation of lactic acid and other acidic anaerobic metabolic by-products in the muscle, causing the stereotypical burning sensation of local muscle fatigue, though recent studies have indicated otherwise, actually finding that lactic acid
8449-416: The factor limiting contractile force. Peripheral muscle fatigue during physical work is considered an inability for the body to supply sufficient energy or other metabolites to the contracting muscles to meet the increased energy demand. This is the most common case of physical fatigue—affecting a national average of 72% of adults in the work force in 2002. This causes contractile dysfunction that manifests in
8568-599: The fast action potentials involved in nerve conduction. Slower action potentials in muscle cells and some types of neurons are generated by voltage-gated calcium channels. Each of these types comes in multiple variants, with different voltage sensitivity and different temporal dynamics. The most intensively studied type of voltage-dependent ion channels comprises the sodium channels involved in fast nerve conduction. These are sometimes known as Hodgkin-Huxley sodium channels because they were first characterized by Alan Hodgkin and Andrew Huxley in their Nobel Prize-winning studies of
8687-532: The feeling of weak or tired muscles in the absence of muscle weakness, that is the muscle can generate a normal amount of force but it is perceived as requiring more effort. General asthenia occurs in many chronic wasting diseases (such as tuberculosis and cancer), sleep disorders or chronic disorders of the heart, lungs or kidneys, and is probably most marked in diseases of the adrenal gland. Asthenia may be limited to certain organs or systems of organs, as in asthenopia , characterized by ready fatiguability. Asthenia
8806-415: The first two postnatal weeks. Several types of cells support an action potential, such as plant cells, muscle cells, and the specialized cells of the heart (in which occurs the cardiac action potential ). However, the main excitable cell is the neuron , which also has the simplest mechanism for the action potential. Neurons are electrically excitable cells composed, in general, of one or more dendrites,
8925-408: The form of a rapid upward (positive) spike followed by a rapid fall. These up-and-down cycles are known as action potentials . In some types of neurons, the entire up-and-down cycle takes place in a few thousandths of a second. In muscle cells, a typical action potential lasts about a fifth of a second. In plant cells , an action potential may last three seconds or more. The electrical properties of
9044-456: The human brain, although they are a distinct minority. The amplitude of an action potential is often thought to be independent of the amount of current that produced it. In other words, larger currents do not create larger action potentials. Therefore, action potentials are said to be all-or-none signals, since either they occur fully or they do not occur at all. This is in contrast to receptor potentials , whose amplitudes are dependent on
9163-454: The incoming sound into the opening and closing of mechanically gated ion channels , which may cause neurotransmitter molecules to be released. In similar manner, in the human retina , the initial photoreceptor cells and the next layer of cells (comprising bipolar cells and horizontal cells ) do not produce action potentials; only some amacrine cells and the third layer, the ganglion cells , produce action potentials, which then travel up
9282-630: The intensity of a stimulus. In both cases, the frequency of action potentials is correlated with the intensity of a stimulus. Despite the classical view of the action potential as a stereotyped, uniform signal having dominated the field of neuroscience for many decades, newer evidence does suggest that action potentials are more complex events indeed capable of transmitting information through not just their amplitude, but their duration and phase as well, sometimes even up to distances originally not thought to be possible. In sensory neurons , an external signal such as pressure, temperature, light, or sound
9401-421: The inward current. A sufficiently strong depolarization (increase in V m ) causes the voltage-sensitive sodium channels to open; the increasing permeability to sodium drives V m closer to the sodium equilibrium voltage E Na ≈ +55 mV. The increasing voltage in turn causes even more sodium channels to open, which pushes V m still further towards E Na . This positive feedback continues until
9520-481: The magnitude of the stimulus. A variety of action potential types exist in many cell types and cell compartments as determined by the types of voltage-gated channels, leak channels , channel distributions, ionic concentrations, membrane capacitance, temperature, and other factors. The principal ions involved in an action potential are sodium and potassium cations; sodium ions enter the cell, and potassium ions leave, restoring equilibrium. Relatively few ions need to cross
9639-497: The mechanism of saltatory conduction was suggested in 1925 by Ralph Lillie, the first experimental evidence for saltatory conduction came from Ichiji Tasaki and Taiji Takeuchi and from Andrew Huxley and Robert Stämpfli. By contrast, in unmyelinated axons, the action potential provokes another in the membrane immediately adjacent, and moves continuously down the axon like a wave. Myelin has two important advantages: fast conduction speed and energy efficiency. For axons larger than
9758-423: The membrane and producing the "falling phase" of the action potential. The depolarized voltage opens additional voltage-dependent potassium channels, and some of these do not close right away when the membrane returns to its normal resting voltage. In addition, further potassium channels open in response to the influx of calcium ions during the action potential. The intracellular concentration of potassium ions
9877-402: The membrane called ion pumps and ion channels . In neurons, the types of ion channels in the membrane usually vary across different parts of the cell, giving the dendrites , axon , and cell body different electrical properties. As a result, some parts of the membrane of a neuron may be excitable (capable of generating action potentials), whereas others are not. Recent studies have shown that
9996-465: The membrane for the membrane voltage to change drastically. The ions exchanged during an action potential, therefore, make a negligible change in the interior and exterior ionic concentrations. The few ions that do cross are pumped out again by the continuous action of the sodium–potassium pump , which, with other ion transporters , maintains the normal ratio of ion concentrations across the membrane. Calcium cations and chloride anions are involved in
10115-422: The membrane in myelinated segments of the axon. However, the current is carried by the cytoplasm, which is sufficient to depolarize the first or second subsequent node of Ranvier . Instead, the ionic current from an action potential at one node of Ranvier provokes another action potential at the next node; this apparent "hopping" of the action potential from node to node is known as saltatory conduction . Although
10234-446: The membrane potential affects the permeability, which then further affects the membrane potential. This sets up the possibility for positive feedback , which is a key part of the rising phase of the action potential. A complicating factor is that a single ion channel may have multiple internal "gates" that respond to changes in V m in opposite ways, or at different rates. For example, although raising V m opens most gates in
10353-417: The membrane potential becomes more negative, returning towards resting potential. The undershoot, or afterhyperpolarization , phase is the period during which the membrane potential temporarily becomes more negatively charged than when at rest (hyperpolarized). Finally, the time during which a subsequent action potential is impossible or difficult to fire is called the refractory period , which may overlap with
10472-418: The membrane potential is raised above a certain level, the channel shows increased probability of transitioning to the activated (open) state. The higher the membrane potential the greater the probability of activation. Once a channel has activated, it will eventually transition to the inactivated (closed) state. It tends then to stay inactivated for some time, but, if the membrane potential becomes low again,
10591-427: The membrane potential up to threshold. When an action potential is triggered, the membrane potential abruptly shoots upward and then equally abruptly shoots back downward, often ending below the resting level, where it remains for some period of time. The shape of the action potential is stereotyped; this means that the rise and fall usually have approximately the same amplitude and time course for all action potentials in
10710-406: The membrane potential. The rapid influx of sodium ions causes the polarity of the plasma membrane to reverse, and the ion channels then rapidly inactivate. As the sodium channels close, sodium ions can no longer enter the neuron, and they are then actively transported back out of the plasma membrane. Potassium channels are then activated, and there is an outward current of potassium ions, returning
10829-475: The membrane potential—this gives rise to the absolute refractory period. Even after a sufficient number of sodium channels have transitioned back to their resting state, it frequently happens that a fraction of potassium channels remains open, making it difficult for the membrane potential to depolarize, and thereby giving rise to the relative refractory period. Because the density and subtypes of potassium channels may differ greatly between different types of neurons,
10948-417: The membrane), the synapse is excitatory. If, however, the binding decreases the voltage (hyperpolarizes the membrane), it is inhibitory. Whether the voltage is increased or decreased, the change propagates passively to nearby regions of the membrane (as described by the cable equation and its refinements). Typically, the voltage stimulus decays exponentially with the distance from the synapse and with time from
11067-417: The most excitable part of a neuron is the part after the axon hillock (the point where the axon leaves the cell body), which is called the axonal initial segment , but the axon and cell body are also excitable in most cases. Each excitable patch of membrane has two important levels of membrane potential: the resting potential , which is the value the membrane potential maintains as long as nothing perturbs
11186-469: The muscle cell. This makes less calcium available for the muscle cell. In addition, the Columbia researchers propose that an enzyme activated by this released calcium eats away at muscle fibers. Substrates within the muscle generally serve to power muscular contractions. They include molecules such as adenosine triphosphate (ATP), glycogen and creatine phosphate . ATP binds to the myosin head and causes
11305-442: The nature of the fatigue-inducing work that is being performed. Though not universally used, "metabolic fatigue" is a common alternative term for peripheral muscle weakness, because of the reduction in contractile force due to the direct or indirect effects of the reduction of substrates or accumulation of metabolites within the myocytes . This can occur through a simple lack of energy to fuel contraction, or through interference with
11424-534: The neurons comprising the autonomous nervous system are not, in general, myelinated. Myelin prevents ions from entering or leaving the axon along myelinated segments. As a general rule, myelination increases the conduction velocity of action potentials and makes them more energy-efficient. Whether saltatory or not, the mean conduction velocity of an action potential ranges from 1 meter per second (m/s) to over 100 m/s, and, in general, increases with axonal diameter. Action potentials cannot propagate through
11543-478: The other phases. The course of the action potential is determined by two coupled effects. First, voltage-sensitive ion channels open and close in response to changes in the membrane voltage V m . This changes the membrane's permeability to those ions. Second, according to the Goldman equation , this change in permeability changes the equilibrium potential E m , and, thus, the membrane voltage V m . Thus,
11662-429: The outward potassium current overwhelms the inward sodium current and the membrane repolarizes back to its normal resting potential around −70 mV. However, if the depolarization is large enough, the inward sodium current increases more than the outward potassium current and a runaway condition ( positive feedback ) results: the more inward current there is, the more V m increases, which in turn further increases
11781-429: The peak of the action potential, while potassium continues to leave the cell. The efflux of potassium ions decreases the membrane potential or hyperpolarizes the cell. For small voltage increases from rest, the potassium current exceeds the sodium current and the voltage returns to its normal resting value, typically −70 mV. However, if the voltage increases past a critical threshold, typically 15 mV higher than
11900-432: The potassium channels are inactivated because of preceding depolarization. On the other hand, all neuronal voltage-activated sodium channels inactivate within several milliseconds during strong depolarization, thus making following depolarization impossible until a substantial fraction of sodium channels have returned to their closed state. Although it limits the frequency of firing, the absolute refractory period ensures that
12019-468: The propagation of action potentials along axons and their termination at the synaptic knobs, it is helpful to consider the methods by which action potentials can be initiated at the axon hillock . The basic requirement is that the membrane voltage at the hillock be raised above the threshold for firing. There are several ways in which this depolarization can occur. Action potentials are most commonly initiated by excitatory postsynaptic potentials from
12138-451: The rate of transitions and the probability per unit time of each type of transition. Voltage-gated ion channels are capable of producing action potentials because they can give rise to positive feedback loops: The membrane potential controls the state of the ion channels, but the state of the ion channels controls the membrane potential. Thus, in some situations, a rise in the membrane potential can cause ion channels to open, thereby causing
12257-460: The resting potential close to E K ≈ –75 mV. Since Na ions are in higher concentrations outside of the cell, the concentration and voltage differences both drive them into the cell when Na channels open. Depolarization opens both the sodium and potassium channels in the membrane, allowing the ions to flow into and out of the axon, respectively. If the depolarization is small (say, increasing V m from −70 mV to −60 mV),
12376-553: The resting state. Each action potential is followed by a refractory period , which can be divided into an absolute refractory period , during which it is impossible to evoke another action potential, and then a relative refractory period , during which a stronger-than-usual stimulus is required. These two refractory periods are caused by changes in the state of sodium and potassium channel molecules. When closing after an action potential, sodium channels enter an "inactivated" state , in which they cannot be made to open regardless of
12495-423: The resting value, the sodium current dominates. This results in a runaway condition whereby the positive feedback from the sodium current activates even more sodium channels. Thus, the cell fires , producing an action potential. The frequency at which a neuron elicits action potentials is often referred to as a firing rate or neural firing rate . Currents produced by the opening of voltage-gated channels in
12614-424: The second or third node. Thus, the safety factor of saltatory conduction is high, allowing transmission to bypass nodes in case of injury. However, action potentials may end prematurely in certain places where the safety factor is low, even in unmyelinated neurons; a common example is the branch point of an axon, where it divides into two axons. Some diseases degrade myelin and impair saltatory conduction, reducing
12733-429: The sense of smell and touch , respectively. However, not all sensory neurons convert their external signals into action potentials; some do not even have an axon. Instead, they may convert the signal into the release of a neurotransmitter , or into continuous graded potentials , either of which may stimulate subsequent neuron(s) into firing an action potential. For illustration, in the human ear , hair cells convert
12852-410: The signal is propagated passively as electrotonic potential . Regularly spaced unmyelinated patches, called the nodes of Ranvier , generate action potentials to boost the signal. Known as saltatory conduction , this type of signal propagation provides a favorable tradeoff of signal velocity and axon diameter. Depolarization of axon terminals , in general, triggers the release of neurotransmitter into
12971-409: The signals generated by the dendrites. Emerging out from the soma is the axon hillock . This region is characterized by having a very high concentration of voltage-activated sodium channels. In general, it is considered to be the spike initiation zone for action potentials, i.e. the trigger zone . Multiple signals generated at the spines, and transmitted by the soma all converge here. Immediately after
13090-419: The sodium channels are fully open and V m is close to E Na . The sharp rise in V m and sodium permeability correspond to the rising phase of the action potential. The critical threshold voltage for this runaway condition is usually around −45 mV, but it depends on the recent activity of the axon. A cell that has just fired an action potential cannot fire another one immediately, since
13209-452: The sodium channels become inactivated . This lowers the membrane's permeability to sodium relative to potassium, driving the membrane voltage back towards the resting value. At the same time, the raised voltage opens voltage-sensitive potassium channels; the increase in the membrane's potassium permeability drives V m towards E K . Combined, these changes in sodium and potassium permeability cause V m to drop quickly, repolarizing
13328-411: The success of saltatory conduction. They should be as long as possible to maximize the speed of conduction, but not so long that the arriving signal is too weak to provoke an action potential at the next node of Ranvier. In nature, myelinated segments are generally long enough for the passively propagated signal to travel for at least two nodes while retaining enough amplitude to fire an action potential at
13447-435: The synaptic knobs. In order to enable fast and efficient transduction of electrical signals in the nervous system, certain neuronal axons are covered with myelin sheaths. Myelin is a multilamellar membrane that enwraps the axon in segments separated by intervals known as nodes of Ranvier . It is produced by specialized cells: Schwann cells exclusively in the peripheral nervous system , and oligodendrocytes exclusively in
13566-472: The system can be quite difficult to work out. Hodgkin and Huxley approached the problem by developing a set of differential equations for the parameters that govern the ion channel states, known as the Hodgkin-Huxley equations . These equations have been extensively modified by later research, but form the starting point for most theoretical studies of action potential biophysics. As the membrane potential
13685-431: The time required for the voltage-activated sodium channels to recover from inactivation, i.e., to return to their closed state. There are many types of voltage-activated potassium channels in neurons. Some of them inactivate fast (A-type currents) and some of them inactivate slowly or not inactivate at all; this variability guarantees that there will be always an available source of current for repolarization, even if some of
13804-409: The voltage-gated sodium channels that will carry the action potential in the mature neurons. The longer opening times for the calcium channels can lead to action potentials that are considerably slower than those of mature neurons. Xenopus neurons initially have action potentials that take 60–90 ms. During development, this time decreases to 1 ms. There are two reasons for this drastic decrease. First,
13923-413: The voltage-sensitive sodium channel, it also closes the channel's "inactivation gate", albeit more slowly. Hence, when V m is raised suddenly, the sodium channels open initially, but then close due to the slower inactivation. The voltages and currents of the action potential in all of its phases were modeled accurately by Alan Lloyd Hodgkin and Andrew Huxley in 1952, for which they were awarded
14042-429: The work was continued at the same intensity. The exact mechanisms of central fatigue are unknown, though there has been considerable interest in the role of serotonergic pathways. Nerves control the contraction of muscles by determining the number, sequence, and force of muscular contraction. When a nerve experiences synaptic fatigue it becomes unable to stimulate the muscle that it innervates. Most movements require
14161-540: The workout. Part of the process of strength training is increasing the nerve's ability to generate sustained, high frequency signals which allow a muscle to contract with their greatest force. It is this "neural training" that causes several weeks worth of rapid gains in strength, which level off once the nerve is generating maximum contractions and the muscle reaches its physiological limit. Past this point, training effects increase muscular strength through myofibrillar or sarcoplasmic hypertrophy and metabolic fatigue becomes
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