Why do membrane potentials occur

Channels for cations positive ions will have negatively charged side chains in the pore. Channels for anions negative ions will have positively charged side chains in the pore. Some ion channels are selective for charge but not necessarily for size. Some ion channels do not allow ions to freely diffuse across the membrane, but are gated instead.

A ligand-gated channel opens because a molecule, or ligand, binds to the extracellular region of the channel Figure A mechanically-gated channel opens because of a physical distortion of the cell membrane.

Many channels associated with the sense of touch are mechanically-gated. For example, as pressure is applied to the skin, mechanically-gated channels on the subcutaneous receptors open and allow ions to enter Figure A voltage-gated channel is a channel that responds to changes in the electrical properties of the membrane in which it is embedded.

Normally, the inner portion of the membrane is at a negative voltage. When that voltage becomes less negative and reaches a value specific to the channel, it opens and allows ions to cross the membrane Figure A leak channel is randomly gated, meaning that it opens and closes at random, hence the reference to leaking.

There is no actual event that opens the channel; instead, it has an intrinsic rate of switching between the open and closed states. Leak channels contribute to the resting transmembrane voltage of the excitable membrane Figure The membrane potential is a distribution of charge across the cell membrane, measured in millivolts mV.

The standard is to compare the inside of the cell relative to the outside, so the membrane potential is a value representing the charge on the intracellular side of the membrane based on the outside being zero, relatively speaking; Figure There is typically an overall net neutral charge between the extracellular and intracellular environments of the neuron.

However, a slight difference in charge occurs right at the membrane surface, both internally and externally. It is the difference in this very limited region that holds the power to generate electrical signals, including action potentials, in neurons and muscle cells. When the cell is at rest, ions are distributed across the membrane in a very predictable way. The cytosol contains a high concentration of anions, in the form of phosphate ions and negatively charged proteins.

With the ions distributed across the membrane at these concentrations, the difference in charge is described as the resting membrane potential. The exact value measured for the resting membrane potential varies between cells, but mV is a commonly reported value. This voltage would actually be much lower except for the contributions of some important proteins in the membrane.

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 balancing ions leaking down their concentration gradient and ions being pumped back up their concentration gradient. Without any outside influence, the resting membrane potential will be maintained. To get an electrical signal started, the membrane potential has to become more positive.

Because sodium is a positively charged ion, as it enters the cell it will change the relative voltage immediately inside the cell membrane. The resting membrane potential is approximately mV, so the sodium cation entering the cell will cause the membrane to become less negative.

This is known as depolarization , meaning the membrane potential moves toward zero becomes less polarized. 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 of the resting potential, but overshoots that value. Other non-excitable cell types that contract due to changes in the RMP include myofibroblasts and ventricular fibroblasts Chilton et al.

The myocardium is composed of different cell types. Cardiac myocytes occupy only a third of the cells in the cardiac myocardium; the remaining non-myocyte cells are mainly endothelial cells, VSMs and fibroblasts Brilla et al.

In myocardial injury, an immune response is generated, which results in the recruitment of fibroblasts which proliferate and transform into myofibroblasts Frangogiannis et al. This results in the depolarisation of the membrane potential and enhances the contractility of the fibroblasts Chilton et al. The role of the membrane potential in contraction is crucial. One such example mentioned above is its modulation of the contraction of VSMs, since failure of the VSMs to contract can lead to detrimental effects in the blood flow to the heart.

The electromechanics of the cochlea are driven by the hair cell RMP reviewed by Ashmore, The cochlea outer hair cells play a key role in sound amplification and fine frequency selectivity that works via two interrelated mechanisms: somatic electromotility Brownell, and the active hair bundle Harland et al.

The cochlea of the mammalian inner ear is filled with two different extracellular solutions, the perilymph and endolymph, separated from each other by hair cells. This is the case with certain forms of albino associated congenital deafness, where there is an absence of the KCNJ10 expressing melanocytes synonymous with intermediate cells in the stria vascularis.

Apparent correlation between the RMP and proliferative potential of cells. The RMP of tumor and non-tumor cells and their proliferation potential are shown. Modified with permission from the copyright holders Yang and Brackenbury The syncytial basolateral surface is mainly provided by fibrocytes in the spiral ligament. In spite of the physiological importance of fibrocytes, the machinery underlying the establishment of this unique RMP have not yet been fully characterized.

The complexities of the cochlea provides an excellent example of different yet distinct roles of the RMP in a functioning non-excitable tissue. The electrochemical profile of the cochlea.

A The structure of the human ear and a cross-section of the cochlea are illustrated in the upper panel. The boxed region in the lower panel is shown in B. The membrane potential across the basolateral and apical surfaces of the syncytial layer, vSB and vSA, respectively, and the basolateral and apical surfaces of the marginal cell layer, vMB and vMA, respectively, are shown.

In all cells, maintenance of cell volume is essential for survival. The membrane potential is likely to be a key regulator of this process in many cells, although, to date this has only been demonstrated explicitly in a few cell types including: cardiomyocytes, retinal Muller cells, and chondrocytes Lewis et al. Active control of cell volume is especially true of chondrocytes, since they exist in an environment with constantly changing osmolality and compressive loads Wilkins et al.

For example, the voltage-gated KV1. Our own examination of the chondrocyte RMP over many years across different species indicates that it is less negative than published for most other cell types.

We proposed that the diverse compliment of chondrocyte ion channels in both articular Barrett-Jolley et al. Our data support this as they show that at negative membrane potentials chondrocytes appear to be unable to decrease their volume when exposed to higher osmotic potential solutions, i. These are a type of glial cell that supports the local homeostasis of the retina.

Further studies by the same group Netti et al. This data indicates that the optimal RMP is unique to different types of cells depending on their function and environment; hence its maintenance is crucial for cell survival.

This system has membrane potential level control of secretion and is perhaps a model of secretion that is more widely known. On the other hand, when the blood glucose levels fall, ATP concentration decrease leading to the opening of the K ATP channels, membrane hyperpolarization and the termination of insulin secretion.

The K ATP channels can also regulate the insulin release through their interaction with phosphoinositides in particular with PIP 2 which stimulates K ATP channels by decreasing their sensitivity to ATP, causing the cells to become more hyperpolarized and not secrete insulin properly when glucose levels are high Lin et al. This highlights the importance of the RMP as mutations in the ion channels that contribute to the RMP can have detrimental effects that lead to disease.

It has been postulated that where cells fall on this scale corresponds to their proliferative potential Figure 1 ; Binggeli and Weinstein, For example, cells that have membrane potentials that are hyperpolarized tend to be quiescent and do not usually undergo mitosis; whereas cells that have depolarised membrane potentials tend to be proliferative and usually mitotically active Cone, However, this is not always the case as each cell type is different and expresses different ion channels.

The membrane potential is highly correlated with mitosis, DNA synthesis, cell cycle progression and overall proliferation in general Cone, ; Binggeli and Weinstein, This effect seems to be the opposite of what is known in other cell types.

Membrane potential control of proliferation is a complex relationship because the membrane potential relies on the activity of many ion channels. 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.

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.

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. 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.