While the mutation centered models of cancer have led the field of research for many years, attention has moved to recognize the importance of the cellular environment. Cancer is fundamentally a developmental disorder of cell regulation, where there is a loss of the organizational capacity of the surrounding environment Chernet and Levin, b ; the RMP is a key element in this environment as the cell membrane is where the cell meets its environment and where it interacts with biomechanical, biochemical, and bioelectrical gradients, all of which impinge the gene regulatory networks.
Here we refer to bioelectrics as the EFs that are produced the spatial and temporal ion flow and sensed by non-excitable cells. A gateway through the cell membrane exists in the form of multiple ion channels that allow the controlled passage of specific ions. As mentioned earlier, the membrane potential is a key biophysical signal in non-excitable cells that regulates important activities such as proliferation and differentiation and is typically cell type specific Table 1.
Cancer differs from normal cells by the relatively depolarized state of its cells Cone, ; Binggeli and Cameron, ; Binggeli and Weinstein, ; even as far back as the late s tumors were detected based on their voltmeter readings Burr et al.
This is very similar in range to non-tumor proliferating cells but not quiescent and more fully differentiated cells that are more polarized. The importance of the membrane potential in differentiation can be seen from the experiments of Sundelacruz et al. Similarly, the depolarization of cells is able to induce a metastatic phenotype.
These melanocytes exhibit properties of metastasis such as over-proliferation, cell shape change that facilitates migration, and colonization of other organs and tissues, but the hyperpolarization of cells is able to inhibit oncogene induced tumorigenesis.
For example, K ir and constitutively open GlyRF99A, hyperpolarized cells and prevented the formation of tumors despite the strong expression of a co-transfected oncogene Xrel3 Chernet and Levin, b ; this was confirmed through the use of several different hyperpolarizing channels, indicating that tumor suppression was due to the RMP rather than any one specific channel. Ion channels are good therapeutic targets see for example, Humphries and Dart, ; however, the RMP is influenced by multiple channels and so it is possible that different combinations of ion channel modulating drugs and biologics may be required to effectively change a given RMP.
One model of cancer formation is the stem-cell model, where specific cancers arise from stem-cell niches e. Changes in the RMP at specific locations appear to act as a source of non-genetic information that affect developmental processes including cancer, and appears to be an untapped treatment mechanism in the war against cancer. Tissue wounding is an interesting phenomenon because the electrical potential generated by the ion movement in healthy tissue is disrupted and a significant EF is generated that is necessary for wound healing Reid and Zhao, Indeed, the EF over-rides other well-accepted physiological cues and initiates directional cell migration into the wounded area.
Wound generated EFs are produced by the directional flow of charged ion species. Some of this ion flux will be due to leakage from damaged cells [which themselves have membrane potential dependent repair mechanisms Luxardi et al.
However, large currents are generated for days after wounding that are not accounted for by immediate injury. Epithelial wounding has been extensively studied, however, little is reported on the role of the membrane potential in response to wounding and healing. The maintenance of the structural integrity of epithelia is crucial to the function of this tissue type, and healing after injury has been described by two major mechanisms, cell migration and cytoskeleton reorganization Chifflet et al.
Chifflet et al. Actin reorganization is evident by the formation of actin cables that form at the leading edge of cells, analogous to the tightening of a purse string as the cells close the wound. The effects of applied EFs in the wound healing process are becoming apparent Nuccitelli, Nuccitelli speculated that when a cell is placed in an EF, the voltage across the plasma membrane will be modified the most in regions that are perpendicular to the EF lines.
The ends of the cell that face the two poles of the field will experience the largest effect. Open channels, however, may result in differential distribution of ions within the cell, with positive ions experiencing a larger force driving them into the cell at the membrane region facing the positive pole of the EF. In cells with membrane potentials that are inherently more depolarized, the effects may be more apparent.
Some fully differentiated cells also have more depolarized RMPs, including chondrocytes Lewis et al. Broken bones have been reported to heal more efficiently when an EF is applied across the break. Thus, in surface wounds or bone damage, a depolarized cell membrane appears to be key in wound healing through epithelial cell and MSC cell migration and cytoskeleton reorganization, respectively.
The ion channels underlying these effects remain to be established. Finally, pigmentation in mammals is generally a membrane potential dependent process. In mammals, pigment cells such as skin and uveal melanocytes, and retinal pigment epithelial RPE cells are non-excitable cells that contain melanosomes which are lysosome-related organelles that synthesize melanin, the main pigment that colors eyes, skin and hair Sulem et al.
Melanin is essential for the protection of the skin and eyes against solar ultraviolet UV radiation. This could initiate the melanin transfer in the skin and hence enable protection of the genetic material of keratinocytes against UV radiation damage. Over the past several years it has become clear that the RMP is far more widely important to biology than just a firing mechanism for action potentials of excitable cells but rather plays a central role in several biological functions.
Modulation of the membrane potential is a potential new target for an additional range of drugs which target a range of diseases and biological functions from cancer through to wound healing and is likely to be key to the development of successful stem cell therapies. The continued exploration of ion channels, which have, in the past been seen as redundant is likely to become increasingly important as these mechanisms are further understood as we seek ever more therapeutic targets.
All authors made substantial contributions to the conception or design of the work and interpretation of data for the work, participated equally in drafting the work or revising it critically for important intellectual content, and approved the content for publication and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
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.
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Deutsch, C. Voltage-gated potassium conductance in human T lymphocytes stimulated with phorbol ester. Djamgoz, M. It takes longer for potassium channels to open. When they do open, potassium rushes out of the cell, reversing the depolarization. Also at about this time, sodium channels start to close. This causes the action potential to go back toward mV a repolarization.
The action potential actually goes past mV a hyperpolarization because the potassium channels stay open a bit too long. Gradually, the ion concentrations go back to resting levels and the cell returns to mV. Lights, Camera, Action Potential This page describes how neurons work. Resting Membrane Potential When a neuron is not sending a signal, it is "at rest.
Action Potential The resting potential tells about what happens when a neuron is at rest. And there you have it Do you like interactive word search puzzles? Read about the physical factors behind the action potential. Nerve Signaling - from NobelPrize.
The giant axon of the squid can be to times larger than a mammalian axon. The giant axon innervates the squid's mantle muscle. These muscles are used to propel the squid through the water. Signal summation occurs when impulses add together to reach the threshold of excitation to fire a neuron. Signal summation at the axon hillock : A single neuron can receive both excitatory and inhibitory inputs from multiple neurons. All these inputs are added together at the axon hillock.
Each neuron connects with numerous other neurons, often receiving multiple impulses from them. Sometimes, a single excitatory postsynaptic potential EPSP is strong enough to induce an action potential in the postsynaptic neuron, but often multiple presynaptic inputs must create EPSPs around the same time for the postsynaptic neuron to be sufficiently depolarized to fire an action potential.
Summation, either spatial or temporal, is the addition of these impulses at the axon hillock. One neuron often has input from many presynaptic neurons, whether excitatory or inhibitory; therefore, inhibitory postsynaptic potentials IPSPs can cancel out EPSPs and vice versa.
The net change in postsynaptic membrane voltage determines whether the postsynaptic cell has reached its threshold of excitation needed to fire an action potential. If the neuron only receives excitatory impulses, it will also generate an action potential. However, if the neuron receives as many inhibitory as excitatory impulses, the inhibition cancels out the excitation and the nerve impulse will stop there.
Spatial summation means that the effects of impulses received at different places on the neuron add up so that the neuron may fire when such impulses are received simultaneously, even if each impulse on its own would not be sufficient to cause firing.
Temporal summation means that the effects of impulses received at the same place can add up if the impulses are received in close temporal succession. Thus, the neuron may fire when multiple impulses are received, even if each impulse on its own would not be sufficient to cause firing. Synaptic plasticity is the strengthening or weakening of synapses over time in response to increases or decreases in their activity.
Plastic change also results from the alteration of the number of receptors located on a synapse. Synaptic plasticity is the basis of learning and memory, enabling a flexible, functioning nervous system.
Synaptic plasticity can be either short-term synaptic enhancement or synaptic depression or long-term. Two processes in particular, long-term potentiation LTP and long-term depression LTD , are important forms of synaptic plasticity that occur in synapses in the hippocampus: a brain region involved in storing memories.
Long-term potentiation and depression : Calcium entry through postsynaptic NMDA receptors can initiate two different forms of synaptic plasticity: long-term potentiation LTP and long-term depression LTD. LTP arises when a single synapse is repeatedly stimulated. The next time glutamate is released from the presynaptic cell, it will bind to both NMDA and the newly-inserted AMPA receptors, thus depolarizing the membrane more efficiently.
LTD occurs when few glutamate molecules bind to NMDA receptors at a synapse due to a low firing rate of the presynaptic neuron. The calcium that does flow through NMDA receptors initiates a different calcineurin and protein phosphatase 1-dependent cascade, which results in the endocytosis of AMPA receptors.
This makes the postsynaptic neuron less responsive to glutamate released from the presynaptic neuron. Short-term synaptic plasticity acts on a timescale of tens of milliseconds to a few minutes.
Short-term synaptic enhancement results from more synaptic terminals releasing transmitters in response to presynaptic action potentials. Synapses will strengthen for a short time because of either an increase in size of the readily- releasable pool of packaged transmitter or an increase in the amount of packaged transmitter released in response to each action potential. Depletion of these readily-releasable vesicles causes synaptic fatigue. Short-term synaptic depression can also arise from post-synaptic processes and from feedback activation of presynaptic receptors.
Long-term potentiation LTP is a persistent strengthening of a synaptic connection, which can last for minutes or hours. These receptors are normally blocked by magnesium ions. Activated AMPA receptors allow positive ions to enter the cell. Therefore, the next time glutamate is released from the presynaptic membrane, it will have a larger excitatory effect EPSP on the postsynaptic cell because the binding of glutamate to these AMPA receptors will allow more positive ions into the cell.
The insertion of additional AMPA receptors strengthens the synapse so that the postsynaptic neuron is more likely to fire in response to presynaptic neurotransmitter release.
Some drugs co-opt the LTP pathway; this synaptic strengthening can lead to addiction. In this situation, calcium that enters through NMDA receptors initiates a different signaling cascade, which results in the removal of AMPA receptors from the postsynaptic membrane. With the decrease in AMPA receptors in the membrane, the postsynaptic neuron is less responsive to the glutamate released from the presynaptic neuron. The weakening and pruning of unused synapses trims unimportant connections, leaving only the salient connections strengthened by long-term potentiation.
Privacy Policy. Skip to main content. The Nervous System. Search for:. How Neurons Communicate. Nerve Impulse Transmission within a Neuron: Resting Potential The resting potential of a neuron is controlled by the difference in total charge between the inside and outside of the cell.
Learning Objectives Explain the formation of the resting potential in neurons. Key Takeaways Key Points When the neuronal membrane is at rest, the resting potential is negative due to the accumulation of more sodium ions outside the cell than potassium ions inside the cell. Potassium ions diffuse out of the cell at a much faster rate than sodium ions diffuse into the cell because neurons have many more potassium leakage channels than sodium leakage channels.
Sodium-potassium pumps move two potassium ions inside the cell as three sodium ions are pumped out to maintain the negatively-charged membrane inside the cell; this helps maintain the resting potential.
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