Further work later explores a range of voltage-gated ion channels involved in this process Rao et al. However, it is also important to note that the downstream events are different for every cell type and can be as a result of voltage or the flow of certain ions across the membrane. Furthermore, it was shown that cells that are post-mitotic such as those in the CNS can be coaxed back to enter the cell cycle after sustained depolarisation. Depolarising astrocytes with ouabain causes their increased proliferation and DNA synthesis MacFarlane and Sontheimer, Contractility of VSMs, as previously mentioned, is regulated by the membrane potential; however, these cells can switch phenotype during injury or development Frid et al.
The different phenotypes have different ion channel expressions. Interestingly, there is a switch in the type of ion channels that are expressed in each phenotype which contribute to the regulation of the membrane potential and hence the contractility of the VSMs phenotype. Furthermore, numerous studies show that cancer cell proliferation is regulated by different ion channel modulators implying a role for the RMP. As well as that, the RMP has also been shown to regulate neuronal differentiation Messenger and Warner, Additionally, the membrane potential also regulates proliferation through the modulation of the cell cycle.
Regulation of the cell cycle through the RMP is further discussed below. As discussed earlier, the membrane potential can regulate proliferation levels within cells through regulating the cell cycle progression.
Membrane potential is the difference in electric potential between the interior and the exterior of a biological cell. With respect to the exterior of the cell, typical values of membrane potential, Biological Membranes: Theory of Transport, Potentials and Electric Impulses. Cambridge University Press (September 26, ). This electrical potential difference is called the membrane potential. [Is this the For a cell's membrane potential, the reference point is the outside of the cell.
A hyperpolarized membrane potential inhibits mitosis as it blocks quiescent cells in the G1 phase of the cell cycle from entering the S phase and hence blocks the DNA synthesis. It is postulated that there may be a threshold RMP level that cells need to overcome in order to drive DNA synthesis in cells. For example the expression of certain ion channels in proliferating astrocytes can be upregulated or downregulated depending on the RMP levels of the cells and the cell cycle stage that they are in.
This indicates that there seems to be a G1 to S phase transition checkpoint that is regulated by the membrane potential. This membrane potential control of the cell cycle can be utilized as a mechanism to inhibit cancer cell proliferation, making it a potential target for future treatments. Since cell cycle and cell proliferation are strongly influenced by the RMP, it is not surprising that cancer, one of the biggest killers in the western world is also closely linked to the RMP.
Cancer is often understood as the interplay between the host organism and individual cell regulation Lobikin et al. 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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They move molecules, products etc. Furthermore, depolarisation of cells does not always lead to activation, in some instances; it can leave cells less excitable; for example, the voltage-gated ion channels that ordinarily underlie the action potentials become inactivated and are no longer available for activation. The chemistry involved in membrane potentials reaches to many scientific disciplines. Ion channel blockers inhibit B cell activation at a precise stage of the G1 phase of the cell cycle. Genetic determinants of hair, eye and skin pigmentation in Europeans.
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Geek, P. Heinz, and B. Evidence against direct coupling between amino acid transport and ATP hydrolysis. Acta — Lev, A. Ionic activities in cells. Bronner and A. However, it can be easily seen that equation 9 can be generalized for more than two ion species. The resting potential is then given by the quotient of two sums over all ion species,. We are now ready to go beyond the equilibrium state and to consider the behavior of a cell when its transmembrane voltage changes over time.
In order to take into account the transients, we have to consider the membrane capacitance. As mentioned, the membrane itself is a quite good electrical isolator which means we can accumulate electrical charges on one side that can then not cross over to the other of course, the same amount of charge with the opposite sign will be found on the other side. Conservation of charge requires that the rate of charge accumulation is equal to the current,. The voltage in a capacitor is proportional to its charge, with the constant of proportionality being the capacity C.
Since C is a constant for an ideal capacitor and to an excellent approximation for a cell membrane as well , we have. Combining the two previous equations, we obtain the following Ordinary Differential Equation for the membrane voltage:. Note that, in equilibrium, the temporal derivative disappears and we get equation 8 again. For time-independent conductances and reversal potentials , it is customary to lump together the ionic conductances and voltages. Indeed, we can write eq. Frequently, eq. So far, we have been considering only conductances that have no voltage or time dependence.
There are many other types of conductances which play a role in neurons. One important class of conductances results from different types of synapses which are responsible for most of the communication between neurons. Another important class of conductances are due to channels that open dependent on the voltage of the cell itself see below. All of these currents have the same form as the leakage current in eq.
For instance, Hodgkin-Huxley type conductances depend on the transmembrane voltage, and they also have their own specific kinetics for opening and closing. There can be a large number of terms of the form 15 , one for each current, and all are added to the right hand side of eq. We have so far considered the electrical activity in a patch of membrane that is small enough or homogeneous enough to behave everywhere the same.
Many neurons are large or inhomogeneous enough that their membranes cannot be described by a single membrane patch. Instead, the interactions between different parts of the cell membrane need to be taken into account. This is the topic of Cable Theory. Ernst Niebur , Scholarpedia, 3 6 Jump to: navigation , search. Post-publication activity Curator: Ernst Niebur Contributors:. Anne-Elise Tobin. Elias August. Sponsored by: Frances K. Categories : Models of Neurons Electrophysiology. Namespaces Page Discussion. Views Read View source View history.