How many transmissions does it normally take for a neuron to reach threshold for action potential?

How many transmissions does it normally take for a neuron to reach threshold for action potential?

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This video illustrates and explains how the dendrite connections being activated causes the neuron to be polarized until it reaches "threshold", and firing. My question is how many times might a neuron's dendrites need to receive "fires" from other neurons in order to reach threshold. I think I understand that it isn't a binary matter, so I realize the answer isn't going to be 5 or 5,000 but a general range.

As a related question, how long does it take for polarization to wear off if additional transmissions don't come in, and if the polarization does wear off, is this wear-off mechanic important to the neural system? Is wearing off a significant aspect of the neural process, in other words?

To give a rough idea, according to my calculations it takes 153 inputs (individual action potentials) from CA3 pyramidal neurons to produce a depolarisation above threshold in the CA1 pyramidal neuron. This is of course a very simplistic division that does not consider spatial and temporal summation or any other complicating factor. Also note that each CA3 pyramidal neuron forms a variable number of synapses onto each CA1 pyramidal neuron (~5? according to the hippocampus book), and for each action potential only some of these synapses release a vesicle. Thus 153 inputs = xxx number of activated synapse (activated synapse = synapse receiving action potential).

So how did I arrive at 153?

According to this paper [1], a single action potential from a CA3 neuron produces an average depolarisation of 131 uV, presumably at the cell body, which we can also take, for simplicity, to be the depolarisation produced at the axon hillock. So assuming the threshold is 20mV (I'm not sure exactly but it should be in the 20-30mV range), the number of CA3 neuron each producing a depolarisation of 131 uV required to reach threshold is 20/0.131=153.

Again this is a simplistic division and may not be a good estimate once you take into account all the complicating factors in summation, but hopefully it gives some idea. Also bear in mind that synapses in different parts of the brain can have very different properties, so 153 might not be applicable to them.

[1] The time course and amplitude of EPSPs evoked at synapses between pairs of CA3/CA1 neurons in the hippocampal slice. RJ Sayer, MJ Friedlander and SJ Redman. Journal of Neuroscience 1 March 1990, 10 (3) 826-836

How many action potential are needed to cause an action potential in the postsynaptic neuron depends on the strength of the synapse(s) involved. It's not possible to answer this question in general.

It is not just the number of action potentials received but also the firing pattern in which they arrive and the location of the synapse(s) on the dendrites/soma (proximal/distal, on a spine or not, on which kind of spine,… ) of the postsynaptic neuron.

However, for some neurons it is possible to trigger an action potential in a postsynaptic neuron with a single action potential. But in this case it is very probable that multiple synapses were involved between the two neurons (example paper).

To your second question: the time until polarization wears off is called the time constant tau of a neuron. It is a property that varies from neuron to neuron and is one of the things that can be measured when recording from a neuron. It is one of the many factors that affects how incoming action potentials are translated into a neuron's output firing.

Threshold potential

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).

Most often, the threshold potential is a membrane potential value between –50 and –55 mV, [1] but can vary based upon several factors. A neuron's resting membrane potential (–70 mV) can be altered to either increase or decrease likelihood of reaching threshold via sodium and potassium ions. An influx of sodium into the cell through open, voltage-gated sodium channels can depolarize the membrane past threshold and thus excite it while an efflux of potassium or influx of chloride can hyperpolarize the cell and thus inhibit threshold from being reached.

How many transmissions does it normally take for a neuron to reach threshold for action potential? - Biology

Neurons & the Nervous System

The human nervous system consists of billions of nerve cells (or neurons)plus supporting (neuroglial) cells. Neurons are able to respond to stimuli (such as touch, sound, light, and so on), conduct impulses, and communicate with each other (and with other types of cells like muscle cells).

The nucleus of a neuron is located in the cell body. Extending out from the cell body are processes called dendrites and axons. These processes vary in number & relative length but always serve to conduct impulses (with dendrites conducting impulses toward the cell body and axons conducting impulses away from the cell body).

Neurons can respond to stimuli and conduct impulses because a membrane potential is established across the cell membrane. In other words, there is an unequal distribution of ions (charged atoms) on the two sides of a nerve cell membrane. This can be illustrated with a voltmeter:

With one electrode placed inside a neuron and the other outside, the voltmeter is 'measuring' the difference in the distribution of ions on the inside versus the outside. And, in this example, the voltmeter reads -70 mV (mV = millivolts). In other words, the inside of the neuron is slightly negative relative to the outside. This difference is referred to as the Resting Membrane Potential. How is this potential established?

The membranes of all nerve cells have a potential difference across them, with the cell interior negative with respect to the exterior (a). In neurons, stimuli can alter this potential difference by opening sodium channels in the membrane. For example, neurotransmitters interact specifically with sodium channels (or gates). So sodium ions flow into the cell, reducing the voltage across the membrane.

Once the potential difference reaches a threshold voltage, the reduced voltage causes hundreds of sodium gates in that region of the membrane to open briefly. Sodium ions flood into the cell, completely depolarizing the membrane (b). This opens more voltage-gated ion channels in the adjacent membrane, and so a wave of depolarization courses along the cell &mdash the action potential.

As the action potential nears its peak, the sodium gates close, and potassium gates open, allowing ions to flow out of the cell to restore the normal potential of the membrane (c) (Gutkin and Ermentrout 2006).

Establishment of the Resting Membrane Potential

Membranes are polarized or, in other words, exhibit a RESTING MEMBRANE POTENTIAL. This means that there is an unequal distribution of ions (atoms with a positive or negative charge) on the two sides of the nerve cell membrane. This POTENTIAL generally measures about 70 millivolts (with the INSIDE of the membrane negative with respect to the outside). So, the RESTING MEMBRANE POTENTIAL is expressed as -70 mV, and the minus means that the inside is negative relative to (or compared to) the outside. It is called a RESTING potential because it occurs when a membrane is not being stimulated or conducting impulses (in other words, it's resting).

What factors contribute to this membrane potential?

Two ions are responsible: sodium (Na+) and potassium (K+). An unequal distribution of these two ions occurs on the two sides of a nerve cell membrane because carriers actively transport these two ions: sodium from the inside to the outside and potassium from the outside to the inside. AS A RESULT of this active transport mechanism (commonly referred to as the SODIUM - POTASSIUM PUMP), there is a higher concentration of sodium on the outside than the inside and a higher concentration of potassium on the inside than the outside (Animation: How the Sodium-Potassium Pump Works).

The Sodium-Potassium Pump
Used with permission of Gary Kaiser


The nerve cell membrane also contains special passageways for these two ions that are commonly referred to as GATES or CHANNELS. Thus, there are SODIUM GATES and POTASSIUM GATES. These gates represent the only way that these ions can diffuse through a nerve cell membrane. IN A RESTING NERVE CELL MEMBRANE, all the sodium gates are closed and some of the potassium gates are open. AS A RESULT, sodium cannot diffuse through the membrane & largely remains outside the membrane. HOWEVER, some potassium ions are able to diffuse out.

OVERALL, therefore, there are lots of positively charged potassium ions just inside the membrane and lots of positively charged sodium ions PLUS some potassium ions on the outside. THIS MEANS THAT THERE ARE MORE POSITIVE CHARGES ON THE OUTSIDE THAN ON THE INSIDE. In other words, there is an unequal distribution of ions or a resting membrane potential. This potential will be maintained until the membrane is disturbed or stimulated. Then, if it's a sufficiently strong stimulus, an action potential will occur.

Voltage sensing in a sodium ion channel. The voltage sensors in a sodium channels are charged 'paddles'
that move through the fluid membrane interior. Voltage sensors (two of which are shown here) are linked mechanically to
the channel's 'gate'. Each voltage sensor has four positive charges (amino acids) (Modified slightly from Sigworth 2003).

In a cross section view of the voltage-dependent potassium channel,
two of the four paddles move up and down, opening and closing the
central pore through which potassium ions flow out of the cell, restoring the
cell's normal negative inside, positive outside polarity.

An action potential is a very rapid change in membrane potential that occurs when a nerve cell membrane is stimulated. Specifically, the membrane potential goes from the resting potential (typically -70 mV) to some positive value (typically about +30 mV) in a very short period of time (just a few milliseconds).

What causes this change in potential to occur? The stimulus causes the sodium gates (or channels) to open and, because there's more sodium on the outside than the inside of the membrane, sodium then diffuses rapidly into the nerve cell. All these positively-charged sodiums rushing in causes the membrane potential to become positive (the inside of the membrane is now positive relative to the outside). The sodium channels open only briefly, then close again.

The potassium channels then open, and, because there is more potassium inside the membrane than outside, positively-charged potassium ions diffuse out. As these positive ions go out, the inside of the membrane once again becomes negative with respect to the outside (Animation: Voltage-gated channels) .

Threshold stimulus & potential

  • Action potentials occur only when the membrane in stimulated (depolarized) enough so that sodium channels open completely. The minimum stimulus needed to achieve an action potential is called the threshold stimulus.
  • The threshold stimulus causes the membrane potential to become less negative (because a stimulus, no matter how small, causes a few sodium channels to open and allows some positively-charged sodium ions to diffuse in).
  • If the membrane potential reaches the threshold potential (generally 5 - 15 mV less negative than the resting potential), the voltage-regulated sodium channels all open. Sodium ions rapidly diffuse inward, & depolarization occurs.

All-or-None Law - action potentials occur maximally or not at all. In other words, there's no such thing as a partial or weak action potential. Either the threshold potential is reached and an action potential occurs, or it isn't reached and no action potential occurs.

    • During an action potential, a second stimulus will not produce a second action potential (no matter how strong that stimulus is)
    • corresponds to the period when the sodium channels are open (typically just a millisecond or less)

      • Another action potential can be produced, but only if the stimulus is greater than the threshold stimulus
      • corresponds to the period when the potassium channels are open (several milliseconds)
      • the nerve cell membrane becomes progressively more 'sensitive' (easier to stimulate) as the relative refractory period proceeds. So, it takes a very strong stimulus to cause an action potential at the beginning of the relative refractory period, but only a slightly above threshold stimulus to cause an action potential near the end of the relative refractory period

      The absolute refractory period places a limit on the rate at which a neuron can conduct impulses, and the relative refractory period permits variation in the rate at which a neuron conducts impulses. Such variation is important because it is one of the ways by which our nervous system recognizes differences in stimulus strength, e.g., dim light = retinal cells conduct fewer impulses per second vs. brighter light = retinal cells conduct more impulses per second.

      How does the relative refractory period permit variation in rate of impulse conduction? Let's assume that the relative refractory period of a neuron is 20 milliseconds long and, further, that the threshold stimulus for that neuron (as determined, for example, in a lab experiment with that neuron) is 0.5 volt. If that neuron is continuously stimulated at a level of 0.5 volt, then an action potential (and impulse) will be generated every 20 milliseconds (because once an action potential has been generated with a threshold stimulus [and ignoring the absolute refractory period], another action potential cannot occur until the relative refractory period is over). So, in this example, the rate of stimulation (and impulse conduction) would be 50 per second (1 sec = 1000 ms 1000 ms divided by 20 ms = 50).

      If we increase the stimulus (e.g., from 0.5 volt to 1 volt), what happens to the rate at which action potentials (and impulses) occur? Because 1 volt is an above-threshold stimulus, it means that, once an actional potential has been generated, another one will occur in less than 20 ms or, in other words, before the end of the relative refractory period. Thus, in our example, the increased stimulus will increase the rate of impulse conduction above 50 per second. Without more information, it's not possible to calculate the exact rate. However, it's sufficient that you understand that increasing stimulus strength will result in an increase in the rate of impulse conduction.

      Impulse conduction - an impulse is simply the movement of action potentials along a nerve cell. Action potentials are localized (only affect a small area of nerve cell membrane). So, when one occurs, only a small area of membrane depolarizes (or 'reverses' potential). As a result, for a split second, areas of membrane adjacent to each other have opposite charges (the depolarized membrane is negative on the outside & positive on the inside, while the adjacent areas are still positive on the outside and negative on the inside). An electrical circuit (or 'mini-circuit') develops between these oppositely-charged areas (or, in other words, electrons flow between these areas). This 'mini-circuit' stimulates the adjacent area and, therefore, an action potential occurs. This process repeats itself and action potentials move down the nerve cell membrane. This 'movement' of action potentials is called an impulse.

      • impulses typically travel along neurons at a speed of anywhere from 1 to 120 meters per second
      • the speed of conduction is influenced by the presence or absence of myelin
      • Neurons with myelin (or myelinated neurons) conduct impulses much faster than those without myelin.

      The myelin sheath (blue) surrounding axons (yellow) is produced by glial cells (Schwann cells in the PNS, oligodendrocytes in the CNS). These cells produce large membranous extensions that ensheath the axons in successive layers that are then compacted by exclusion of cytoplasm (black) to form the myelin sheath. The thickness of the myelin sheath (the number of wraps around the axon) is proportional to the axon's diameter.

      Myelination, the process by which glial cells ensheath the axons of neurons in layers of myelin, ensures the rapid conduction of electrical impulses in the nervous system. The formation of myelin sheaths is one of the most spectacular examples of cell-cell interaction and coordination in nature. Myelin sheaths are formed by the vast membranous extensions of glial cells: Schwann cells in the peripheral nervous system (PNS) and oligodendrocytes in the central nervous system (CNS). The axon is wrapped many times (like a Swiss roll) by these sheetlike membrane extensions to form the final myelin sheath, or internode. Internodes can be as long as 1 mm and are separated from their neighbors by a short gap (the node of Ranvier) of 1 micrometer. The concentration of voltage-dependent sodium channels in the axon membrane at the node, and the high electrical resistance of the multilayered myelin sheath, ensure that action potentials jump from node to node (a process termed "saltatory conduction") (ffrench-Constant 2004).

      Schwann cells (or oligodendrocytes) are located at regular intervals along the process (axons and, for some neurons, dendrites) & so a section of a myelinated axon would look like this:

      Between areas of myelin are non-myelinated areas called the nodes of Ranvier. Because fat (myelin) acts as an insulator, membrane coated with myelin will not conduct an impulse. So, in a myelinated neuron, action potentials only occur along the nodes and, therefore, impulses 'jump' over the areas of myelin - going from node to node in a process called saltatory conduction (with the word saltatory meaning 'jumping'):

      Because the impulse 'jumps' over areas of myelin, an impulse travels much faster along a myelinated neuron than along a non-myelinated neuron.

      Types of Neurons - the three main types of neurons are:



      Bipolar neuron

      Multipolar neurons are so-named because they have many (multi-) processes that extend from the cell body: lots of dendrites plus a single axon. Functionally, these neurons are either motor (conducting impulses that will cause activity such as the contraction of muscles) or association (conducting impulses and permitting 'communication' between neurons within the central nervous system).

      Unipolar neurons have but one process from the cell body. However, that single, very short, process splits into longer processes (a dendrite plus an axon). Unipolar neurons are sensory neurons - conducting impulses into the central nervous system.

      Bipolar neurons have two processes - one axon & one dendrite. These neurons are also sensory. For example, biopolar neurons can be found in the retina of the eye.

      Neuroglial, or glial, cells - general functions include:

      1 - forming myelin sheaths
      2 - protecting neurons (via phagocytosis)
      3 - regulating the internal environment of neurons
      in the central nervous system

      Synapse = point of impulse transmission between neurons impulses are transmitted from pre-synaptic neurons to post-synaptic neurons

      Synapses usually occur between the axon of a pre-synaptic neuron & a dendrite or cell body of a post-synaptic neuron. At a synapse, the end of the axon is 'swollen' and referred to as an end bulb or synaptic knob. Within the end bulb are found lots of synaptic vesicles (which contain neurotransmitter chemicals) and mitochondria (which provide ATP to make more neurotransmitter). Between the end bulb and the dendrite (or cell body) of the post-synaptic neuron, there is a gap commonly referred to as the synaptic cleft. So, pre- and post-synaptic membranes do not actually come in contact. That means that the impulse cannot be transmitted directly. Rather, the impulse is transmitted by the release of chemicals called chemical transmitters (or neurotransmitters).

      Micrograph of a synapse (Schikorski and Stevens 2001).

      Post-synaptic membrane receptors

      Structural features of a typical nerve cell (i.e., neuron) and synapse. This drawing shows the major components of a typical neuron, including the cell body with the nucleus the dendrites that receive signals from other neurons and the axon that relays nerve signals to other neurons at a specialized structure called a synapse. When the nerve signal reaches the synapse, it causes the release of chemical messengers (i.e., neurotransmitters) from storage vesicles. The neurotransmitters travel across a minute gap between the cells and then interact with protein molecules (i.e., receptors) located in the membrane surrounding the signal-receiving neuron. This interaction causes biochemical reactions that result in the generation, or prevention, of a new nerve signal, depending on the type of neuron, neurotransmitter, and receptor involved (Goodlett and Horn 2001).

      When an impulse arrives at the end bulb, the end bulb membrane becomes more permeable to calcium. Calcium diffuses into the end bulb & activates enzymes that cause the synaptic vesicles to move toward the synaptic cleft. Some vesicles fuse with the membrane and release their neurotransmitter (a good example of exocytosis). The neurotransmitter molecules diffuse across the cleft and fit into receptor sites in the postsynaptic membrane. When these sites are filled, sodium channels open & permit an inward diffusion of sodium ions. This, of course, causes the membrane potential to become less negative (or, in other words, to approach the threshold potential). If enough neurotransmitter is released, and enough sodium channels are opened, then the membrane potential will reach threshold. If so, an action potential occurs and spreads along the membrane of the post-synaptic neuron (in other words, the impulse will be transmitted). Of course, if insufficient neurotransmitter is released, the impulse will not be transmitted.

      Impulse transmission - The nerve impulse (action potential) travels down the presynaptic axon towards the synapse, where it activates voltage-gated calcium channels leading to calcium influx, which triggers the simultaneous release of neurotransmitter molecules from many synaptic vesicles by fusing the membranes of the vesicles to that of the nerve terminal. The neurotransmitter molecules diffuse across the synaptic cleft, bind briefly to receptors on the postsynaptic neuron to activate them, causing physiological responses that may be excitatory or inhibitory depending on the receptor. The neurotransmitter molecules are then either quickly pumped back into the presynaptic nerve terminal via transporters, are destroyed by enzymes near the receptors (e.g. breakdown of acetylcholine by cholinesterase), or diffuse into the surrounding area.

      This describes what happens when an 'excitatory' neurotransmitter is released at a synapse. However, not all neurotransmitters are 'excitatory.'

      Types of neurotransmitters:

        1- Excitatory - neurotransmitters that make membrane potential less negative (via increased permeability of the membrane to sodium) &, therefore, tend to 'excite' or stimulate the postsynaptic membrane

      2 - Inhibitory - neurotransmitters that make membrane potential more negative (via increased permeability of the membrane to potassium) &, therefore, tend to 'inhibit' (or make less likely) the transmission of an impulse. One example of an inhibitory neurotransmitter is gamma aminobutyric acid (GABA shown below). Medically, GABA has been used to treat both epilepsy and hypertension. Another example of an inhibitory neurotransmitter is beta-endorphin, which results in decreased pain perception by the CNS.

      Neurotransmitters (acetylcholine described starting at about 2:55)

        1 - Temporal summation - transmission of an impulse by rapid stimulation of one or more pre-synaptic neurons

      2 - Spatial summation - transmission of an impulse by simultaneous or nearly simultaneous stimulation of two or more pre-synaptic neurons

      Literature cited

      ffrench-Constant, C., H. Colognato, and R. J. M. Franklin. 2004. Neuroscience: the mysteries of myelin unwrapped. Science 304:688-689.

      Goodlett, C.R., and K. H. Horn. 2001. Mechanisms of alcohol-induced damage to the developing nervous system. Alcohol Research & Health 25:175&ndash184.

      Gutkin, B. and G. B. Ermentrout. 2006. Neuroscience: spikes too kinky in the cortex? Nature 440: 999-1000.

      Sigworth, F. J. 2003. Structural biology: life's transistors. Nature 423:21-22.

      Zhou, M., João H. Morais-Cabral, Sabine Mann and Roderick MacKinnon. 2001. Potassium channel receptor site for the inactivation gate and quaternary amine inhibitors. Nature 411:657-661.

      During the Action Potential

      You’ve decided that you are thirsty and would like a drink of water. Your brain starts the chain of events to send a message to the muscles in your hand that you need to pick up the glass.

      When a nerve impulse (which is how neurons communicate with one another) is sent out from a cell body, the sodium channels in the cell membrane open and the positive sodium cells surge into the cell.

      Once the cell reaches a certain threshold, an action potential will fire, sending the electrical signal down the axon. The sodium channels play a role in generating the action potential in excitable cells and activating a transmission along the axon.

      Action potentials either happen or they don't there is no such thing as a "partial" firing of a neuron. This principle is known as the all-or-none law.

      This means that neurons always fire at their full strength. This ensures that the full intensity of the signal is carried down the nerve fiber and transferred to the next cell and that the signal does not weaken or become lost the further it travels from the source.

      The message from the brain is now traveling down the nerves to the muscles in the hand.

      Hyperpolarization and Return to Resting Potential

      Action potentials are considered an &ldquoall-or nothing&rdquo event. Once the threshold potential is reached, the neuron completely depolarizes. As soon as depolarization is complete, the cell &ldquoresets&rdquo its membrane voltage back to the resting potential. The Na + channels close, beginning the neuron&rsquos refractory period. At the same time, voltage-gated K + channels open, allowing K + to leave the cell. As K + ions leave the cell, the membrane potential once again becomes negative. The diffusion of K + out of the cell hyperpolarizes the cell, making the membrane potential more negative than the cell&rsquos normal resting potential. At this point, the sodium channels return to their resting state, ready to open again if the membrane potential again exceeds the threshold potential. Eventually, the extra K + ions diffuse out of the cell through the potassium leakage channels, bringing the cell from its hyperpolarized state back to its resting membrane potential.

      Major Neurotransmitters and Receptors

      At least 100 substances can act as neurotransmitters about 18 are of major importance. Several occur in slightly different forms. Neurotransmitters can be grouped in different classes, such as

      Small molecules (eg, glutamate, gamma-aminobutyric acid, glycine, adenosine , acetylcholine, serotonin, histamine, noradrenaline)

      Neuropeptides (eg, endorphins)

      Gaseous molecules (eg, nitric oxide, carbon monoxide)

      Glutamate and aspartate

      These amino acids are the major excitatory neurotransmitters in the CNS. They occur in the cortex, cerebellum, and spinal cord. In neurons, synthesis of nitric oxide (NO) increases in response to glutamate. Excess glutamate can be toxic, increasing intracellular calcium, free radicals, and proteinase activity. These neurotransmitters may contribute to tolerance to opioid therapy and mediate hyperalgesia.

      Glutamate receptors are classified as NMDA (N-methyl- d -aspartate) receptors and non-NMDA receptors. Phencyclidine (PCP, also known as angel dust) and memantine (used to treat Alzheimer disease) bind to NMDA receptors.

      Gamma-aminobutyric acid

      Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain. It is an amino acid derived from glutamate, which is decarboxylated by glutamate decarboxylase. After interaction with its receptors, GABA is actively pumped back into nerve terminals and metabolized. Glycine, which resembles GABA in its action, occurs principally in interneurons (Renshaw cells) of the spinal cord and in circuits that relax antagonist muscles.

      GABA receptors are classified as GABA-A (activating chloride channels) and GABA-B (potentiating cAMP formation). GABA-A receptors are the site of action for several neuroactive drugs, including benzodiazepines, barbiturates, picrotoxin, and muscimol. Alcohol also binds to GABA-A receptors. GABA-B receptors are activated by baclofen , used to treat muscle spasms (eg, in multiple sclerosis).


      Serotonin (5-hydroxytryptamine, or 5-HT) is generated by the raphe nucleus and midline neurons of the pons and upper brain stem. Tryptophan is hydroxylated by tryptophan hydroxylase to 5-hydroxytryptophan, then decarboxylated to serotonin. Serotonin levels are controlled by the uptake of tryptophan and intraneuronal monoamine oxidase (MAO), which breaks down serotonin. Ultimately, serotonin is excreted in the urine as 5-hydroxyindoacetic acid or 5-HIAA.

      Serotoninergic (5-HT) receptors (with at least 15 subtypes) are classified as 5-HT1 (with 4 subtypes), 5-HT2, and 5-HT3. Selective serotonin receptor agonists (eg, sumatriptan ) can abort migraines.


      Acetylcholine is the major neurotransmitter of the bulbospinal motor neurons, autonomic preganglionic fibers, postganglionic cholinergic (parasympathetic) fibers, and many neurons in the CNS (eg, basal ganglia, motor cortex). It is synthesized from choline and acetyl coenzyme A by choline acetyltransferase, and its action is rapidly terminated via local hydrolysis to choline and acetate by acetylcholinesterase. Acetylcholine levels are regulated by choline acetyltransferase and by choline uptake. Levels of this neurotransmitter are decreased in patients with Alzheimer disease.

      Cholinergic receptors are classified as nicotinic N1 (in the adrenal medulla and autonomic ganglia) or N2 (in skeletal muscle) or muscarinic M1 through M5 (widely distributed in the CNS). M1 occurs in the autonomic nervous system, striatum, cortex, and hippocampus M2 occurs in the autonomic nervous system, heart, intestinal smooth muscle, hindbrain, and cerebellum.


      Dopamine interacts with receptors on some peripheral nerve fibers and many central neurons (eg, in the substantia nigra, midbrain, ventral tegmental area, and hypothalamus). The amino acid tyrosine is taken up by dopaminergic neurons and converted by tyrosine hydroxylase to 3,4-dihydroxyphenylalanine (dopa), which is decarboxylated by aromatic- l -amino-acid decarboxylase to dopamine . After release and interaction with receptors, dopamine is actively pumped back (reuptake) into the nerve terminal. Tyrosine hydroxylase and MAO (which breaks down dopamine ) regulate dopamine levels in nerve terminals.

      Dopaminergic receptors are classified as D1 through D5. D3 and D4 receptors play a role in thought control (limiting the negative symptoms of schizophrenia) D2 receptor activation controls the extrapyramidal system. However, receptor affinity does not predict functional response (intrinsic activity). For example, ropinirole , which has high affinity for the D3 receptor, has intrinsic activity via activation of D2 receptors.


      Norepinephrine is the neurotransmitter of most postganglionic sympathetic fibers and many central neurons (eg, in the locus caeruleus and hypothalamus). The precursor tyrosine is converted to dopamine , which is hydroxylated by dopamine beta-hydroxylase to norepinephrine . After release and interaction with receptors, some norepinephrine is degraded by catechol O-methyltransferase (COMT), and the remainder is actively taken back into the nerve terminal, where it is degraded by MAO. Tyrosine hydroxylase, dopamine beta-hydroxylase, and MAO regulate intraneuronal norepinephrine levels.

      Adrenergic receptors are classified as alpha-1 (postsynaptic in the sympathetic system), alpha-2 (presynaptic in the sympathetic system and postsynaptic in the brain), beta-1 (in the heart), or beta-2 (in other sympathetically innervated structures).

      Endorphins and enkephalins

      Endorphins and enkephalins are opioids.

      Endorphins are large polypeptides that activate many central neurons (eg, in the hypothalamus, amygdala, thalamus, and locus caeruleus). The cell body contains a large polypeptide called pro-opiomelanocortin, the precursor of alpha-, beta-, and gamma-endorphins. Pro-opiomelanocortin is transported down the axon and cleaved into fragments one is beta-endorphin, contained in neurons that project to the periaqueductal gray matter, limbic structures, and major catecholamine-containing neurons in the brain. After release and interaction with receptors, beta-endorphin is hydrolyzed by peptidases.

      Enkephalins include met-enkephalin and leu-enkephalin, which are small polypeptides present in many central neurons (eg, in the globus pallidus, thalamus, caudate, and central gray matter). Their precursor, proenkephalin, is formed in the cell body, then split by specific peptidases into the active peptides. These substances are also localized in the spinal cord, where they modulate pain signals. The neurotransmitters of pain signals in the posterior horn of the spinal cord are glutamate and substance P. Enkephalins decrease the amount of neurotransmitter released and hyperpolarize (make more negative) the postsynaptic membrane, reducing the generation of action potentials and pain perception at the level of the postcentral gyrus. After release and interaction with peptidergic receptors, enkephalins are hydrolyzed into smaller, inactive peptides and amino acids. Rapid inactivation of exogenous enkephalins prevents these substances from being clinically useful. More stable molecules (eg, morphine ) are used as analgesics instead.

      Endorphin-enkephalin (opioid) receptors are classified as mu-1 and mu-2 (affecting sensorimotor integration and analgesia), delta-1 and delta-2 (affecting motor integration, cognitive function, and analgesia), and kappa-1, kappa-2, and kappa-3 (affecting water balance regulation, analgesia, and food intake). Sigma receptors, currently classified as nonopioid and mostly localized in the hippocampus, bind PCP. New data suggest the presence of many more receptor subtypes, with pharmacologic implications. Components of the molecular precursor to the receptor protein can be rearranged during receptor synthesis to produce several receptor variants (eg, 27 splice variants of the mu opioid receptor). Also, two receptors can combine (dimerize) to form a new receptor.

      Other neurotransmitters

      Dynorphins are a group of 7 peptides with similar amino acid sequences. They, like enkephalins, are opioids.

      Substance P, a peptide, occurs in central neurons (in the habenula, substantia nigra, basal ganglia, medulla, and hypothalamus) and is highly concentrated in the dorsal root ganglia. Its release is triggered by intense afferent painful stimuli. It modulates the neural response to pain and mood it modulates nausea and vomiting through the activation of NK1A receptors that are localized in the brain stem.

      Nitric oxide (NO) is a labile gas that mediates many neuronal processes. It is generated from arginine by NO synthase. Neurotransmitters that increase intracellular calcium (eg, substance P, glutamate, acetylcholine) stimulate NO synthesis in neurons that express NO synthetase. NO may be an intracellular messenger it may diffuse out of a cell into a second neuron and produce physiologic responses (eg, long-term potentiation [strengthening of certain presynaptic and postsynaptic responses—a form of learning]) or enhance glutamate (NMDA-receptor–mediated) neurotoxicity (eg, in Parkinson disease, stroke, or Alzheimer disease).

      Substances with less firmly established roles in neurotransmission include histamine, vasopressin , vasoactive intestinal peptide, carnosine, bradykinin, cholecystokinin, bombesin, somatostatin, corticotropin -releasing factor, neurotensin, and possibly adenosine .

      Endocannabinoids are endogenous lipid-based neurotransmitters that modulate brain, endocrine, and immune system function.

      Nerve Impulse Transmission within a Neuron

      For the nervous system to function, neurons must be able to send and receive signals. These signals are possible because each neuron has a charged cellular membrane (a voltage difference between the inside and the outside), and the charge of this membrane can change in response to neurotransmitter molecules released from other neurons and environmental stimuli. To understand how neurons communicate, one must first understand the basis of the baseline or “resting” membrane charge.

      Neuronal Charged Membranes

      The lipid bilayer membrane that surrounds a neuron is impermeable to charged molecules or ions. To enter or exit the neuron, ions must pass through special proteins called ion channels that span the membrane. Ion channels have different configurations: open, closed, and inactive, as illustrated in Figure 1. Some ion channels need to be activated in order to open and allow ions to pass into or out of the cell. These ion channels are sensitive to the environment and can change their shape accordingly. Ion channels that change their structure in response to voltage changes are called voltage-gated ion channels. Voltage-gated ion channels regulate the relative concentrations of different ions inside and outside the cell. The difference in total charge between the inside and outside of the cell is called the membrane potential.

      Figure 1. Voltage-gated ion channels open in response to changes in membrane voltage. After activation, they become inactivated for a brief period and will no longer open in response to a signal.

      This video discusses the basis of the resting membrane potential.

      Resting Membrane Potential

      A neuron at rest is negatively charged: the inside of a cell is approximately 70 millivolts more negative than the outside (−70 mV, note that this number varies by neuron type and by species). This voltage is called the resting membrane potential it is caused by differences in the concentrations of ions inside and outside the cell. If the membrane were equally permeable to all ions, each type of ion would flow across the membrane and the system would reach equilibrium. Because ions cannot simply cross the membrane at will, there are different concentrations of several ions inside and outside the cell, as shown in Table 1.

      Table 1. Ion Concentration Inside and Outside Neurons
      Ion Extracellular concentration (mM) Intracellular concentration (mM) Ratio outside/inside
      Na + 145 12 12
      K+ 4 155 0.026
      Cl − 120 4 30
      Organic anions (A−) 100

      The resting membrane potential is a result of different concentrations inside and outside the cell. The difference in the number of positively charged potassium ions (K + ) inside and outside the cell dominates the resting membrane potential (Figure 2).

      Figure 2. The (a) resting membrane potential is a result of different concentrations of Na + and K + ions inside and outside the cell. A nerve impulse causes Na + to enter the cell, resulting in (b) depolarization. At the peak action potential, K + channels open and the cell becomes (c) hyperpolarized.

      When the membrane is at rest, K + ions accumulate inside the cell due to a net movement with the concentration gradient. The negative resting membrane potential is created and maintained by increasing the concentration of cations outside the cell (in the extracellular fluid) relative to inside the cell (in the cytoplasm). The negative charge within the cell is created by the cell membrane being more permeable to potassium ion movement than sodium ion movement. In neurons, potassium ions are maintained at high concentrations within the cell while sodium ions are maintained at high concentrations outside of the cell. The cell possesses potassium and sodium leakage channels that allow the two cations to diffuse down their concentration gradient.

      However, the neurons have far more potassium leakage channels than sodium leakage channels. Therefore, potassium diffuses out of the cell at a much faster rate than sodium leaks in. Because more cations are leaving the cell than are entering, this causes the interior of the cell to be negatively charged relative to the outside of the cell. The actions of the sodium potassium pump help to maintain the resting potential, once established. Recall that sodium potassium pumps brings two K + ions into the cell while removing three Na + ions per ATP consumed. As more cations are expelled from the cell than taken in, the inside of the cell remains negatively charged relative to the extracellular fluid. It should be noted that calcium ions (Cl – ) tend to accumulate outside of the cell because they are repelled by negatively-charged proteins within the cytoplasm.

      Action Potential

      A neuron can receive input from other neurons and, if this input is strong enough, send the signal to downstream neurons. Transmission of a signal between neurons is generally carried by a chemical called a neurotransmitter. Transmission of a signal within a neuron (from dendrite to axon terminal) is carried by a brief reversal of the resting membrane potential called an action potential. When neurotransmitter molecules bind to receptors located on a neuron’s dendrites, ion channels open. At excitatory synapses, this opening allows positive ions to enter the neuron and results in depolarization of the membrane—a decrease in the difference in voltage between the inside and outside of the neuron. A stimulus from a sensory cell or another neuron depolarizes the target neuron to its threshold potential (-55 mV). Na + channels in the axon hillock open, allowing positive ions to enter the cell (Figure 2 and Figure 3).

      Once the sodium channels open, the neuron completely depolarizes to a membrane potential of about +40 mV. Action potentials are considered an “all-or nothing” event, in that, once the threshold potential is reached, the neuron always completely depolarizes. Once depolarization is complete, the cell must now “reset” its membrane voltage back to the resting potential. To accomplish this, the Na + channels close and cannot be opened. This begins the neuron’s refractory period, in which it cannot produce another action potential because its sodium channels will not open. At the same time, voltage-gated K + channels open, allowing K + to leave the cell. As K + ions leave the cell, the membrane potential once again becomes negative. The diffusion of K + out of the cell actually hyperpolarizes the cell, in that the membrane potential becomes more negative than the cell’s normal resting potential. At this point, the sodium channels will return to their resting state, meaning they are ready to open again if the membrane potential again exceeds the threshold potential. Eventually the extra K + ions diffuse out of the cell through the potassium leakage channels, bringing the cell from its hyperpolarized state, back to its resting membrane potential.

      Practice Question

      The formation of an action potential can be divided into five steps, which can be seen in Figure 3.

      Figure 3. Action Potential

      1. A stimulus from a sensory cell or another neuron causes the target cell to depolarize toward the threshold potential.
      2. If the threshold of excitation is reached, all Na + channels open and the membrane depolarizes.
      3. At the peak action potential, K + channels open and K + begins to leave the cell. At the same time, Na + channels close.
      4. The membrane becomes hyperpolarized as K + ions continue to leave the cell. The hyperpolarized membrane is in a refractory period and cannot fire.
      5. The K + channels close and the Na + /K + transporter restores the resting potential.

      Potassium channel blockers, such as amiodarone and procainamide, which are used to treat abnormal electrical activity in the heart, called cardiac dysrhythmia, impede the movement of K + through voltage-gated K + channels. Which part of the action potential would you expect potassium channels to affect?

      Figure 4. The action potential is conducted down the axon as the axon membrane depolarizes, then repolarizes.

      Myelin and the Propagation of the Action Potential

      For an action potential to communicate information to another neuron, it must travel along the axon and reach the axon terminals where it can initiate neurotransmitter release. The speed of conduction of an action potential along an axon is influenced by both the diameter of the axon and the axon’s resistance to current leak. Myelin acts as an insulator that prevents current from leaving the axon this increases the speed of action potential conduction. In demyelinating diseases like multiple sclerosis, action potential conduction slows because current leaks from previously insulated axon areas.

      Figure 5. Nodes of Ranvier are gaps in myelin coverage along axons. Nodes contain voltage-gated K + and Na + channels. Action potentials travel down the axon by jumping from one node to the next.

      The nodes of Ranvier, illustrated in Figure 5 are gaps in the myelin sheath along the axon. These unmyelinated spaces are about one micrometer long and contain voltage gated Na + and K + channels. Flow of ions through these channels, particularly the Na + channels, regenerates the action potential over and over again along the axon. This ‘jumping’ of the action potential from one node to the next is called saltatory conduction. If nodes of Ranvier were not present along an axon, the action potential would propagate very slowly since Na + and K + channels would have to continuously regenerate action potentials at every point along the axon instead of at specific points. Nodes of Ranvier also save energy for the neuron since the channels only need to be present at the nodes and not along the entire axon.

      BIOL235: Midterm I

      A) Muscle tissue is specialized for contraction and generation of force.

      B) Epithelial tissue forms glands.

      C) Nervous tissue is specialized for transmission of electrical impulses.

      D) Connective tissue is specialized for exchange between the internal and external environments.

      A. Only nerve and muscle cells have a potential difference across the membrane at rest

      B. It requires very few ions to be distributed unevenly

      C. It has the same value in all cells

      D. It changes dramatically while the cell is at rest

      increase transmitter release into cleft

      block transmitter release

      inhibit transmitter synthesis

      block transmitter reuptake

      block cleft enzymes that metabolize transmitter

      bind to receptor to block or mimic transmitter action

      A. Acetylcholine binds to cholinergic receptors

      B. Acetylcholine binds to nicotinic and muscarinic receptors

      C. Acetylcholine synthesis is catalyzed by acetylcholinesterase

      D. Both acetylcholine binds to cholinergic receptors and acetylcholine binds to nicotinic and muscarinic receptors are correct

      Action Potential

      Action potentials are the electrical pulses that allow the transmission of information within nerves. An action potential represents a change in electrical potential from the resting potential of the neuronal cell membrane, and involves a series of electrical and underlying chemical changes that travel down the length of a neural cell (neuron). The neural impulse is created by the controlled development of action potentials that sweep down the body (axon) of a neural cell.

      There are two major control and communication systems in the human body, the endocrine system and the nervous system. In many respects, the two systems compliment each other. Although long duration effects are achieved through endocrine hormonal regulation, the nervous system allows nearly immediate control, especially regulation of homeostatic mechanisms (e.g., blood pressure regulation).

      The neuron cell structure is specialized so that at one end, there is a flared structure termed the dendrite. At the dendrite, the neuron is able to process chemical signals from other neurons and endocrine hormones. If the signals received at the dendritic end of the neuron are of a sufficient strength and properly timed, they are transformed into action potentials that are then transmitted in a "one-way" direction (unidirectional propagation) down the axon.

      In neural cells, electrical potentials are created by the separation of positive and negative electrical charges that are carried on ions (charged atoms) across the cell membrane. There are a greater number of negatively charged proteins on the inside of the cell, and unequal distribution of cations (positively charged ions) on both sides of the cell membrane. Sodium ions (Na+) are, for example, much more numerous on the outside of the cell than on the inside. The normal distribution of charge represents the resting membrane potential (RMP) of a cell. Even in the rest state there is a standing potential across the membrane and, therefore, the membrane is polarized (contains an unequal distribution of charge). The inner cell membrane is negatively charged relative to the outer shell membrane. This potential difference can be measured in millivolts (mv or mvolts). Measurements of the resting potential in a normal cell average about 70 mv.

      The standing potential is maintained because, although there are both electrical and concentration gradients (a range of high to low concentration) that induce the excess sodium ions to attempt to try to enter the cell, the channels for passage are closed and the membrane remains almost impermeable to sodium ion passage in the rest state.

      The situation is reversed with regard to potassium ion (K+) concentration. The concentration of potassium ions is approximately 30 times greater on the inside of the cell than on the outside. The potassium concentration and electrical gradient forces trying to move potassium out of the cell are approximately twice the strength of the sodium ion gradient forces trying to move sodium ions into the cell. Because, however, the membrane is more permeable to potassium passage, the potassium ions leak through he membrane at a greater rate than sodium enters. Accordingly, there is a net loss of positively charges ions from the inner part of the cell membrane, and the inner part of the membrane carries a relatively more negative charge than the outer part of the cell membrane. These differences result in the net RMP of &minus70mv.

      The structure of the cell membrane, and a process termed the sodium-potassium pump maintains the neural cell RMP. Driven by an ATPase enzyme, the sodium potassium pump moves three sodium ions from the inside of the cell for every two potassium ions that it brings back in. The ATPase is necessary because this movement or pump of ions is an active process that moves sodium and potassium ions against the standing concentration and electrical gradients. Equivalent to moving water uphill against a gravitational gradient, such action requires the expenditure of energy to drive the appropriate pumping mechanism.

      When a neuron is subjected to sufficient electrical, chemical, or in some cases physical or mechanical stimulus that is greater than or equal to a threshold stimulus, there is a rapid movement of ions, and the resting membrane potential changes from &minus70mv to +30mv. This change of approximately 100mv is an action potential that then travels down the neuron like a wave, altering the RMP as it passes.

      The creation of an action potential is an "all or none" event. Accordingly, there are no partial action potentials. The stimulus must be sufficient and properly timed to create an action potential. Only when the stimulus is of sufficient strength will the sodium and potassium ions begin to migrate done their concentration gradients to reach what is termed threshold stimulus and then generate an action potential.

      The action potential is characterized by three specialized phases described as depolarization, repolarization, and hyperpolarization. During depolarization, the 100mv electrical potential change occurs. During depolarization, the neuron cannot react to additional stimuli and this inability is termed the absolute refractory period. Also during depolarization, the RMP of &minus70mv is reestablished. When the RMP becomes more negative than usual, this phase is termed hyperpolarization. As repolarization proceeds, the neuron achieves an increasing ability to respond to stimuli that are greater than the threshold stimulus, and so undergoes a relative refractory period.

      The opening of selected channels in the cell membrane allows the rapid movement of ions down their respective electrical and concentration gradients. This movement continues until the change in charge is sufficient to close the respective channels. Because the potassium ion channels in the cell membrane are slower to close than the sodium ion channels, however, there is a continues loss of potassium ion form the inner cell that leads to hyperpolarization.

      The sodium-potassium pump then restores and maintains the normal RMP.

      In demyelinated nerve fibers, the depolarization induces further depolarization in adjacent areas of the membrane. In myelinated fibers, a process termed salutatory conduction allows transmission of an action potential, despite the insulating effect of the myelin sheath. Because of the sheath, ion movement takes place only at the Nodes of Ranvier. The action potential jumps from node to node along the myelinated axon. Differing types of nerve fibers exhibit different speed of action potential conduction. Larger fibers (also with decreased electrical resistance) exhibit faster transmission than smaller diameter fibers).

      The action potential ultimately reaches the presynaptic portion of the neuron, the terminal part of the neuron adjacent to the next synapse in the neural pathway). The synapse is the gap or intercellular space between neurons. The arrival of the action potential causes the release of ions and chemicals (neurotransmitters) that travel across the synapse and act as the stimulus to create another action potential in the next neuron.

      Synapses: how neurons communicate with each other

      Neurons talk to each other across synapses. When an action potential reaches the presynaptic terminal, it causes neurotransmitter to be released from the neuron into the synaptic cleft, a 20–40nm gap between the presynaptic axon terminal and the postsynaptic dendrite (often a spine).

      After travelling across the synaptic cleft, the transmitter will attach to neurotransmitter receptors on the postsynaptic side, and depending on the neurotransmitter released (which is dependent on the type of neuron releasing it), particular positive (e.g. Na + , K + , Ca + ) or negative ions (e.g. Cl - ) will travel through channels that span the membrane.

      Synapses can be thought of as converting an electrical signal (the action potential) into a chemical signal in the form of neurotransmitter release, and then, upon binding of the transmitter to the postsynaptic receptor, switching the signal back again into an electrical form, as charged ions flow into or out of the postsynaptic neuron.

      An action potential, or spike, causes neurotransmitters to be released across the synaptic cleft, causing an electrical signal in the postsynaptic neuron. (Image: By Thomas Splettstoesser / CC BY-SA 4.0)

      How many transmissions does it normally take for a neuron to reach threshold for action potential? - Biology

      Neurons are electrically excitable, reacting to input via the production of electrical impulses, propagated as action potentials throughout the cell and its axon. These action potentials are generated and propagated by changes to the cationic gradient (mainly sodium and potassium) across their plasma membranes. These action potentials finally reach the axonal terminal and cause depolarization of neighboring cells through synapses. This action is the way these cells can interact with each other, i.e., at synapses via synaptic transmission. Normally, the cell&rsquos interior is negative, compared to its outside. This state is the resting membrane potential of about -60mV. A neuronal action potential gets generated when the negative inside potential reaches the threshold (less negative). This change in membrane potential will open voltage-gated cationic channel (sodium channel) resulting in the process of depolarization and generation of the neuronal action potential. Neuronal action potentials are vital for propagation of impulses along any nerve fiber even at a distance. They also are crucial for communication among neurons through synapses. Disruption of this mechanism can have drastic effects resulting in lack of impulse generation and conduction, illustrated by various neurotoxins and demyelinating disorders.[1][2]

      Structure and Function

      The neuron&rsquos membrane potential gets generated via a difference in the concentration of charged ions. The lipid bilayer of the neuronal cell membrane acts as a capacitor, the transmembrane channels as resistors. This resting (steady-state) potential is critical for the neuron&rsquos physiological state, maintained by an unequal distribution of ions across the cellular membrane and established by ATP-dependent pumps--most notably, sodium-potassium antiporters. These exchangers are responsible for pumping sodium out of the cells into the extracellular space, potassium into the intracellular compartment. When opened, various channels allow permeable ions to flow down their electrochemical gradients, thereby altering the membrane potential. The gating of these channels is by second messengers, neurotransmitters, or voltage changes. Voltage-gated cationic channels are the main channels used in the generation and propagation of neuronal action potential.

      There are 100 billion neurons in the human brain, and there are a quadrillion synapses in the human brain. Any neuron will have on average of 1000 synapses which influence the electrical potential of the membrane. When the resting membrane potential (-60mV) becomes less negative, it depolarizes. When it is more negative, it hyperpolarizes. Upon collating the various movements of ions, particularly the entering of sodium, the cell may have sufficient signals to reach the threshold potential and achieves this threshold by sufficient positively charged ions entering the cell, i.e., terminating the polarity in what is called depolarization. At normal body temperature, the equilibrium potential for sodium is +55 mV, -103 mV for potassium. There are three stages in the generation of the action potential: (1) depolarization, changing the membrane&rsquos potential from -60 mV to +40 mV primarily caused by sodium influx (2) repolarization, a return to the membrane&rsquos resting potential, primarily caused by potassium efflux and (3) after-hyperpolarization, a recovery from a slight overshoot of the repolarization.[3] (see table below)  As mentioned, stage 1 is guided by an increased membrane permeability to sodium. Accordingly, the removal of extracellular sodium, or inactivation of sodium channels, prevents the generation of action potentials.[4] Immediately after an action potential generates, the neuron cannot immediately generate another action potential this is the absolute refractory period. At this moment, the sodium channels are inactivated and remain closed, whereas the potassium channels are still open. This state is followed by the relative refractory period when the neuron may only generate an action potential with a much higher threshold. Thie opens when some of the sodium channels are ready to be opened, and many are still inactivated, whereas some potassium channels are still open as well. The duration of the refractory periods will determine how fast an action potential may be generated and propagated. The propagation of the action potential continues until termination at a synapse, where it can either cause the release of neurotransmitters or conduction of ionic currents. The latter occurs at electrical synapses, whereby presynaptic and postsynaptic cells connect and avoid the use of neurotransmitters.[5] Neurotransmitters are the norm, however, and get released at chemical synapses and neuromuscular junctions.[6] 

      Local currents created by depolarization along a portion of the neuronal membrane, if sufficiently strong, can depolarize neighboring segments of the membrane to the threshold, thereby propagating the action threshold down the membrane and along the neuron&rsquos axon. The determining factor in the speed of this propagation is primarily the extent to which the initial local currents first spread before creating further depolarizations. Factors influencing this speed include the membrane&rsquos electrical resistance and internal contents of the axon. Wider axons have lower internal resistance, and having more voltage-gated sodium channels in the membrane decreases membrane resistance as well. Higher internal resistance and lower membrane resistance contribute to slower action potential propagations. Because the body does not have enough space, instead of making large axons, the nervous system, to maximize propagation velocity, employs glial cells, specifically oligodendrocytes and Schwann cells, to wrap themselves around axons, creating myelin sheaths. These sheaths contribute to greater membrane resistance, patching up areas where channels would otherwise leak. Still, the action potential can only propagate so far before requiring more sodium channels to perpetuate the potential, creating gaps in the myelin sheath called nodes of Ranvier. These nodes have high concentrations of those channels to restart the action potential along the axon, termed saltatory conduction.[1]

      Neuron Action Potential - see the table in media below.

      Clinical Significance

      The rapid depolarization or the upstroke of the neuronal action potential occurs as a result of the opening of the voltage-gated sodium channels. These channels are large transmembrane proteins with different subunits encoded by ten mammalian genes. Problems with these channels are collectively called channelopathies. The channelopathies may affect any excitable tissues, including neurons, skeletal, and cardiac muscles resulting in multiple different diseases. The neurological channelopathies present more commonly in different muscle diseases and the brain. Paramyotonia congenita results from mutations in the gene coding for the alpha-1 subunit of the sodium channel. Sodium channelopathies in the brain result in various forms of refractory epilepsy disorders.

      There is a variety of neurotoxins that can block the action potential. One such deadly toxin is tetrodotoxin (TTX), which inhibits sodium channels.[7] The naturally occurring toxin is normally ingested orally from pufferfish, a part of Japanese cuisine, and its incidence has spread beyond Southeast Asia to the Pacific and Mediterranean, as well as finding this toxin in many other species. By binding to sodium channels and inactivating them, tissues affected are rendered immobile and insensitive. The onset/severity of symptoms arising from TTX correlates on how much an individual consumes, and patients may first present with paraesthesias of the tongue/lips. This presentation is associated with or followed by headache/vomiting that may become muscle weakness and ataxia. Other symptoms include diarrhea, dizziness, and loss of reflexes. Death can occur from respiratory and/or heart failure. Of some clinical significance, however, TTX has some analgesic activity that has been the topic of study in treating pain, and a low dose may reduce heroin craving. Unfortunately, TTX has no cure and is often fatal, with observation and supportive care being the only treatment. Respiratory support comes in the form of endotracheal intubation or mechanical ventilation to support breathing. Early stages of poisoning can be treated with activated charcoal to adsorb the toxin before gastric absorption and with gastric lavage to reduce symptom severity.[8]

      Ciguatoxin is a potent sodium channel blocker that causes a rapid onset of numbness, paraesthesia, dysaesthesia, and muscle paralysis. Ciguatoxins (CTX) are marine neurotoxins that are produced by the dinoflagellates. CTX works by blocking the voltage-gated sodium channels. Humans are exposed to CTX by ingestion of carnivore coral reef fishes, including grouper, red snapper, and barracuda, which feed on fish that have consumed the dinoflagellates.


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