F Profile of the AP waveform in a model of mammalian myelinated axon using parameters from McIntyre et al. The height of the AP is only slightly lower outside of lipid rafts. Therefore, the membrane potential over the inter-raft region is roughly constant, and equal to that over lipid rafts. Note that in myelinated axons, the amplitude of APs over the internodal regions is also not much lower than the amplitude in nodes of Ranvier Bakiri et al.
This is also confirmed by our simulations of a mammalian myelinated axon model see Figure 3F , based on data from McIntyre et al. AP waveforms are slightly wider over lipid rafts in both deterministic Figure 3A and stochastic Figure 3B simulations.
We investigated the influence of the length l of rafts, and the distance between them L on the shape of action potential. The results are plotted in Figure 4. Both AP width and height seem affected by the size and placement of lipid rafts. Longer rafts increase the width of APs almost linearly Figure 4A. Increasing the distance between lipid rafts, on the other hand, shortens the width of APs.
With 0. Figure 4. Action potential height and width as functions of channel distributions. While varying the inter-raft distance, the lipid raft length was set to 0. We treat this question in Section 3. The change in the shape of APs directly results into changes in their metabolic cost Figure 5. Increasing the distance between rafts also reduces the metabolic cost. The profile of the variation in metabolic cost closely follows that of change in AP width, suggesting that width, rather than height, determines the metabolic cost of firing APs Figures 4A,C , 5.
Figure 5. Metabolic cost of action potentials as functions of lipid raft configuration in a 0. Lipid raft length was set to 0. In our simulation, this does not result in a significant change of metabolic cost. In stochastic simulations, the opening of a channel means that a conductance equal to that of the single channel is added to the membrane. This minimum current due to the discrete nature of ion channel conductance has an impact on the metabolic cost of APs.
Figure 6. Metabolic cost of action potentials for different channel distributions in a 0. Data was obtained using both deterministic blue lines and stochastic boxes simulations. On each box, the central mark is the median, the edges of the box are the 25th and 75th percentiles, the whiskers extend to the most extreme data points not considered outliers, and outliers are plotted individually.
Shortening the lipid rafts to 0. Due to their very small diameter, it is extremely difficult to obtain intracellular data from C-fibers, and therefore we can only estimate the propagation velocity in these fibers using extracellular recordings Tigerholm et al.
These estimations can not be reliably linked to axonal diameter. C-fiber axons are known for their very low conduction velocities. In stochastic simulations, we obtained a comparable median value. However, as was the case with the metabolic cost of APs, shortening lipid rafts or increasing the distance between them resulted in a reduction of the AP propagation velocity. Figure 7. Propagation velocity of action potentials for different channel distributions in a 0.
D Uniform distribution. This difference can be attributed to the lowered inward ionic current. In axons, membrane current not only depolarizes the local membrane, but it also serves to drive the waveform of APs forward.
In the most extreme case we considered, with 0. In this axon, stochastically simulated APs fail to propagate in 3 trials out of Figure 8. Action potential and sodium current waveform in uniform channel density axons Blue, STD shaded light blue, deterministic results in blue dotted line , in 0. We can also explain the lower metabolic cost of APs in stochastic simulations compared to deterministic simulations of the same axon Figure 6. Figure 9. Using our data, we can estimate the efficiency of AP propagation in C-fiber axons.
For the 0. Figure Efficiency of action potentials for different channel distributions in a 0. The axon with uniformly distributed ion channels is consuming almost 50 times the capacitive minimum current necessary to charge its membrane to AP peak. The least inefficient axon in this figure still is 20 times more expensive than the theoretical minimum. To check if this inefficiency is specific to the axon, we simulated a simple spherical membrane using the same ion channel densities and physiological data than the axon.
We then compare the AP waveform in the spherical compartment and the axon in Figure Note that the recorded APs were elicited by a rather long current injection in the cell. This inefficiency factor is much larger than even notably inefficient axons such as the squid giant axon Hodgkin, ; Vetter et al. A Simulated and recorded action potentials and B sodium current waveform in a uniform channel density axon Black and in a soma Red.
The green curve in A is reproduced from Figure 6 in Baker The recorded AP is elicited by a long period of current injection, and therefore the membrane potential before the AP is not representative of the true resting potential, reported to be mV. The AP is wider and more metabolically expensive in the axon. Difference of inactivation kinetics between Nav1. Action potentials in this model are much shorter than with the original kinetics for Nav1.
These calculations take into account the difference in the amplitudes of APs between the two models. The reactivation of even a small number of channels maintains the membrane potential in a depolarized state longer.
This in turn opposes the repolarization of the membrane, leaving more time for the possible opening of other channels. This positive feedback effect makes APs slightly wider in stochastic simulations, where the possible stochastic opening of channels is taken into account. The discretization of ion channel conductances amplifies this effect, by increasing the minimum conductance.
Since the effect of the opening of each channel is bigger in smaller axons Faisal et al. Our simulations lead to two new findings regarding the metabolic cost of propagating APs in C-fibers. First, incomplete inactivation of Nav1. This in turn creates very wide APs, which are metabolically very expensive. This value is higher than 4, previously obtained for squid giant axon channels Hodgkin, ; Attwell and Laughlin, , and much higher than the very metabolically efficient channel kinetics Alle et al.
However, the latter kinetics are obtained in higher temperatures and these comparisons should only be used as an illustration. Although incomplete inactivation has been shown to allow fast spiking Carter and Bean, , it is not clear why slow firing fibers such as C-fibers exhibit the same phenomena.
Presumably, the very slow firing rates of these high-threshold fibers reduce the impact of metabolic cost of signaling in C-fibers. The very wide APs may have a functional role by ensuring a strong post-synaptic response Klein and Kandel, ; Augustine, , and thus prioritize APs carried by C-fibers.
Another explanation may be that incomplete deactivation plays a role in ensuring transmission of APs in noise-prone thin fibers.
It is possible that these channels allow for lower Nav1. The role of the Nav1. More detailed simulations are needed to test this hypothesis. We also find that the cost of propagating APs in axons is significantly higher than that of an AP in a spherical membrane compartment. In our simulations, the cost of propagating action potentials in axons is roughly three times the cost estimated at the soma.
The higher cost is associated with wider APs in the axon than in the soma. This is in stark contrast with myelinated axons, where the myelin sheath lowers the capacitance and leak conductance of the membrane. As a result, nodes of Ranvier can be placed much further apart. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Akopian, A. The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways. Alle, H. Energy-efficient action potentials in hippocampal mossy fibers. Science , — Attwell, D. An energy budget for signaling in the grey matter of the brain. Blood Flow Metab. Augustine, G. How does calcium trigger neurotransmitter release? Baker, M. Bakiri, Y. Morphological and electrical properties of oligodendrocytes in the white matter of the corpus callosum and cerebellum.
Black, J. Freeze-fracture ultrastructure of rat C. Expression of Nav1. Pain Sodium channel Nav1. Brain Res. Campero, M. Partial reversal of conduction slowing during repetitive stimulation of single sympathetic efferents in human skin. Acta Physiol. Carter, B. Sodium entry during action potentials of mammalian neurons: incomplete inactivation and reduced metabolic efficiency in fast-spiking neurons.
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Faisal, A. This may appear to be a waste of energy, but each has a role in maintaining the membrane potential. Resting membrane potential describes the steady state of the cell, which is a dynamic process that is balanced by ion leakage and ion pumping.
Without any outside influence, it will not change. To get an electrical signal started, the membrane potential has to change. Because sodium is a positively charged ion, it will change the relative voltage immediately inside the cell relative to immediately outside.
The resting potential is the state of the membrane at a voltage of mV, so the sodium cation entering the cell will cause it to become less negative. This is known as depolarization , meaning the membrane potential moves toward zero. The electrical gradient also plays a role, as negative proteins below the membrane attract the sodium ion.
These channels are specific for the potassium ion. This is called repolarization , meaning that the membrane voltage moves back toward the mV value of the resting membrane potential. Repolarization returns the membrane potential to the mV value that indicates the resting potential, but it actually overshoots that value.
What has been described here is the action potential, which is presented as a graph of voltage over time in Figure 8. It is the electrical signal that nervous tissue generates for communication. That can also be written as a 0. To put that value in perspective, think about a battery.
An AA battery that you might find in a television remote has a voltage of 1. The change seen in the action potential is one or two orders of magnitude less than the charge in these batteries. In fact, the membrane potential can be described as a battery. A charge is stored across the membrane that can be released under the correct conditions. What happens across the membrane of an electrically active cell is a dynamic process that is hard to visualize with static images or through text descriptions.
View this animation to learn more about this process. And what is similar about the movement of these two ions? The question is, now, what initiates the action potential? The description above conveniently glosses over that point.
But it is vital to understanding what is happening. The membrane potential will stay at the resting voltage until something changes. Instead, it means that one kind of channel opens.
Whether it is a neurotransmitter binding to its receptor protein or a sensory stimulus activating a sensory receptor cell, some stimulus gets the process started. Sodium starts to enter the cell and the membrane becomes less negative. The channels that start depolarizing the membrane because of a stimulus help the cell to depolarize from mV to mV. This is what is known as the threshold. Any depolarization that does not change the membrane potential to mV or higher will not reach threshold and thus will not result in an action potential.
Also, any stimulus that depolarizes the membrane to mV or beyond will cause a large number of channels to open and an action potential will be initiated. Because of the threshold, the action potential can be likened to a digital event—it either happens or it does not. If the threshold is not reached, then no action potential occurs.
Also, those changes are the same for every action potential, which means that once the threshold is reached, the exact same thing happens. Stronger stimuli will initiate multiple action potentials more quickly, but the individual signals are not bigger.
Thus, for example, you will not feel a greater sensation of pain, or have a stronger muscle contraction, because of the size of the action potential because they are not different sizes. The action potential is initiated at the beginning of the axon, at what is called the initial segment. Because of this, depolarization spreading back toward previously opened channels has no effect. The action potential must propagate toward the axon terminals; as a result, the polarity of the neuron is maintained, as mentioned above.
Propagation, as described above, applies to unmyelinated axons. When myelination is present, the action potential propagates differently. Because there is not constant opening of these channels along the axon segment, the depolarization spreads at an optimal speed. The distance between nodes is the optimal distance to keep the membrane still depolarized above threshold at the next node. If the nodes were any closer together, the speed of propagation would be slower.
Propagation along an unmyelinated axon is referred to as continuous conduction ; along the length of a myelinated axon, it is saltatory conduction. Along with the myelination of the axon, the diameter of the axon can influence the speed of conduction.
This concept is known as resistance and is generally true for electrical wires or plumbing, just as it is true for axons, although the specific conditions are different at the scales of electrons or ions versus water in a river. Once in the synaptic cleft, the neurotransmitter diffuses the short distance to the postsynaptic membrane of the next neuron and interacts with neurotransmitter receptors on the dendrites or cell body.
Receptors are specific for the neurotransmitter, and the two fit together like a key and lock. One neurotransmitter binds to its receptor and will not bind to receptors for other neurotransmitters, making the binding a specific chemical event Figure 8.
Glial cells, especially astrocytes, are responsible for maintaining the chemical environment of the CNS tissue. The concentrations of ions in the extracellular fluid are the basis for how the membrane potential is established and changes in electrochemical signaling.
If the balance of ions is upset, drastic outcomes are possible. But when the level is far out of balance, the effects can be irreversible. Astrocytes can become reactive in cases such as these, which impairs their ability to maintain the local chemical environment. The glial cells enlarge and their processes swell. When that is lost, the cell cannot get the energy it needs.
In the central nervous system, carbohydrate metabolism is the only means of producing ATP. Elsewhere in the body, cells rely on carbohydrates, lipids, or amino acids to power mitochondrial ATP production. But the CNS does not store lipids in adipocytes fat cells as an energy reserve. The lipids in the CNS are in the cell membranes of neurons and glial cells, notably as an integral component of myelin. Proteins in the CNS are crucial to neuronal function, in roles such as channels for electrical signaling or as part of the cytoskeleton.
Those macromolecules are not used to power mitochondrial ATP production in neurons. For proteins to function correctly, they are dependent on their three-dimensional shape. The linear sequence of amino acids folds into a three-dimensional shape that is based on the interactions between and among those amino acids.
When the folding is disturbed, and proteins take on a different shape, they stop functioning correctly. But the disease is not necessarily the result of functional loss of these proteins; rather, these altered proteins start to accumulate and may become toxic. Diseases of other organ systems can fall into this group as well, such as cystic fibrosis or type 2 diabetes. Recognizing the relationship between these diseases has suggested new therapeutic possibilities.
Interfering with the accumulation of the proteins, and possibly as early as their original production within the cell, may unlock new ways to alleviate these devastating diseases. Visit this site to see a virtual neurophysiology lab, and to observe electrophysiological processes in the nervous system, where scientists directly measure the electrical signals produced by neurons. Often, the action potentials occur so rapidly that watching a screen to see them occur is not helpful.
These action potentials are firing so fast that it sounds like static on the radio. Electrophysiologists can recognize the patterns within that static to understand what is happening. Why is the leech model used for measuring the electrical activity of neurons instead of using humans?
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