Divyan Bavan
Every cell has a resting membrane potential (RMP): the product of an unequal distribution of charge across the cell membrane. The primary ion responsible for this is potassium. The cell has a very high concentration of potassium relative to the extracellular space, meaning there is a strong driving force for potassium to exit the cell. As it does this, it leaves negatively charged proteins and anions—which cannot leave the cell membrane—in the cell. This leaves the intracellular fluid negatively charged compared to the outside of the cell, creating the RMP (Berne and Levy, 2017). By harnessing this potential, cells can facilitate functions such as secondary active transport and the rate of proliferation. Furthermore, some cells rely on the RMP for specific functions such as pigmentation, wound healing, and action potentials. Despite the diversity of these processes, all cells still rely on the same fundamental strategy for generating the RMP. Through an analysis of how it is generated, and what its function is, it is easy to see how critical the RMP is for the body.
There are three properties of the cell which contribute to the generation of the RMP: the potassium ion gradient, membrane selectivity, and the presence of negative charges. As mentioned previously, there is a high concentration of potassium ions in the intracellular fluid compared to the extracellular space. This is a product of the sodium potassium pump, which actively transports three sodium ions out of the cell and two potassium ions in. The result of this is an intracellular concentration of potassium ions of about 120mM, while the extracellular concentration has about 4mM. Conversely, the intracellular concentration of sodium ions is about 14mM while the extracellular concentration is 140mM. While the unequal transport of potassium and sodium ions does create a charge difference across the membrane, this is relatively small (only a few millivolts). To generate the majority of the RMP, the cell must utilize the established chemical gradient to drive an electrical gradient (Berne and Levy, 2017; Chrysafides et al., 2023).
To generate this electrical gradient, potassium must leave the cell without sodium entering, as that would simply balance the charge. The primary cellular structure behind this is the cell membrane. This constituent—which is composed of a phospholipid bilayer—is semi-permeable, meaning that the movement of certain molecules will be favoured over others. For example, due to the hydrophobicity of the fatty acid tails of the phospholipids, ions cannot pass through the membrane unassisted (Berne and Levy, 2017). This explains how the sodium and potassium gradients are maintained. To facilitate the specific efflux of potassium ions, however, the membrane has ion channels. These proteins come in many variations, but have three properties which differentiate them: selectivity, conductance, and gating (Berne and Levy, 2017; Alberts et al., 2002). There are a plethora of ion channels expressed on the cell membrane which exclusively transport and conduct large amounts of potassium ions. A subset of these channels also lacks voltage-gating—the two pore domain K+ (K2P) “leak” channels. While they can be regulated by other factors such as pH, the K2P channels are not affected by the cell’s existing membrane potential. This leaves them open most of the time, creating high permeability for potassium ions (Enyedi et al., 2010; Kuang et al., 2015). This differs from sodium channels, as most of these channels are either voltage or ligand-gated, which means that they are not open at rest. For this reason, sodium ions have 20 to 45 times less permeability across the cell membrane than potassium ions (Henley, 2021).
Since potassium can effectively follow its gradient and leave the cell, and sodium cannot counterbalance the loss of positive charge, this leaves a negatively charged intracellular environment. This is created by proteins which contain negatively charged amino acids (aspartate and glutamate) and organic phosphates (Chrysafides et al., 2023). As more potassium ions leave the cell, the negative charge increases, and the potential difference grows. However, the driving force for the potassium ions, which determines their movement across the membrane, relies on electrical forces too. As more potassium ions leave the cell, the negative charges become stronger and start to pull on the positively charged ions (Wright et al., 2004). The point at which the chemical and electrical forces balance is governed by the Nernst equation, which states that the maximum potential difference created by potassium is around -90mV (Chrysafides et al., 2023). However, in most cases, the cell never reaches this. This is due to the presence of minimal, but significant sodium and chlorine leakage, which depolarizes the cell. To account for this, the Goldman-Hodgkin-Katz equation is used to incorporate the effects of all three ions on the membrane potential. In neurons, this can be calculated to get the resting membrane potential of -70mV (Wright et al., 2004; Chrysafides et al, 2023; Berne and Levy, 2017). However, it should be noted that different cells can vary in RMP, with a range of approximately -10mV to -100mV, the effects of which will be described later in this essay (Kadir et al., 2018).
Now that it is understood how the resting membrane potential is generated, its functions can be explored in detail. These include several processes universal to all cells. One example of this is secondary active transport. This process couples the movement of ions along their electrochemical gradient to the transport of other molecules. This differs from primary active transport, which is seen in the sodium potassium pump, as instead of ATP being the source of energy, it is the electrochemical energy stored in the ionic gradient. An example of a secondary active transporter is the sodium-calcium exchanger. This protein transports 3 sodium ions into the cell and one calcium cell out. This is energetically favourable because the sodium ions are moving down their electrochemical gradient; the energy created by the current and potential difference powers the transport of calcium out of the cell. This process is used to transport many molecules and ions: calcium, glucose, and chloride to name a few (Chen et al., 2022). Finally, membrane potential also plays a role in the rate of proliferation of a cell. As mentioned previously, cells can vary in RMP from -10mV to -100mV (the latter exceeds the equilibrium potential of potassium through several mechanisms such as increased sodium-potassium pump expression). Through studies, it has been shown that a hyperpolarized RMP leads to decreased or halted proliferation, whereas a depolarized RMP leads to increased proliferation. For this reason, hyperpolarization is seen in non-dividing cells such as neurons, while depolarization is common amongst cancer cells (Kadir, 2018).
As previously mentioned, the RMP also plays roles in specific cells. Examples of these functions include action potentials in excitable cells, pigmentation in melanocytes, and hearing in the cochlea. Action potentials are created by depolarizing an excitable cell from its RMP to the point where voltage-gated sodium channels are open. This increases the permeability of the cell to sodium, creating an influx of sodium ions and rapid depolarization of the cell. This electrical signal can travel down axons in neurons, and cause contraction of the sarcoplasm in skeletal muscle tissue (Berne and Levy, 2017). Beyond this classic example, however, the RMP also plays more niche roles in overall body function. Pigmentation is an example of this; depolarization of melanocytes creates a sustained presence of Ca2+, which increases the production of melanin (Kadir et al., 2018). Finally, the RMP also plays an important role in hearing. The cochlea has two main extracellular fluid compartments: the perilymph and endolymph. While the perilymph is standard extracellular fluid, the endolymph has a much higher concentration of positively charged potassium. Combined with a negatively charged intracellular environment in the hair cells of the cochlea, this creates a very large potential difference. This is what creates the fine-tuned sounds in the ear (Kadir et al., 2018).
Through the analysis of how the RMP is generated and its role within the cell, it is easy to understand how critical it is for our body. In its simplest form, the RMP functions as a difference in ionic composition across the cell membrane. However, this simple definition fractally expands into various complexities including selective ion channels, secondary active transporters, and organ-level functions. To fully understand the RMP, scientists have worked for decades to decode its mechanisms, with research still going on about how it impacts the cellular landscape. These discoveries can translate into bases for therapeutic development, as seen with our observation that RMP depolarization can lead to increased proliferation among cancer cells. Due to its multi-disciplinary nature—involving biology, chemistry, physics, and math—our continued study of the resting membrane potential will be based around collaborative research, aiming to discover the fundamental properties of cells and how we can harness them in disease treatment.
References
Abdul Kadir, L., Stacey, M. and Barrett-Jolley, R. (2018). Emerging Roles of the Membrane Potential: Action Beyond the Action Potential. Frontiers in Physiology, 9. doi:https://doi.org/10.3389/fphys.2018.01661.
Alberts, B., Johnson, A., Lewis, J., Raff, M., Roberts, K. and Walter, P. (2002). Ion Channels and the Electrical Properties of Membranes. Molecular Biology of the Cell. 4th edition, [online] 4(1). Available at: https://www.ncbi.nlm.nih.gov/books/NBK26910/.
Chen, I. and Lui, F. (2022). Physiology, Active Transport. [online] PubMed. Available at: https://www.ncbi.nlm.nih.gov/books/NBK547718/.
Chrysafides, S.M. and Sharma, S. (2019). Physiology, Resting Potential. [online] National Library of Medicine. Available at: https://www.ncbi.nlm.nih.gov/books/NBK538338/.
Enyedi, P. and Czirják, G. (2010). Molecular Background of Leak K+ Currents: Two-Pore Domain Potassium Channels. Physiological Reviews, 90(2), pp.559–605. doi:https://doi.org/10.1152/physrev.00029.2009.
Henley, C. (2021). The Membrane at Rest. openbooks.lib.msu.edu. [online] Available at: https://openbooks.lib.msu.edu/neuroscience/chapter/the-membrane-at-rest/.
Koeppen, B.M. and Stanton, B.A. (2017). Berne and Levy Physiology. 7th ed. Saintt Louis Elsevier Health Sciences.
Kuang, Q., Purhonen, P. and Hebert, H. (2015). Structure of potassium channels. Cellular and Molecular Life Sciences, [online] 72(19), pp.3677–3693. doi:https://doi.org/10.1007/s00018-015-1948-5.
Mukherjee, A., Huang, Y., Jens Elgeti, Oh, S., Abreu, J.G., Anjali Rebecca Neliat, Janik Schüttler, Su, D.-D., Dupre, C., Benites, N.C., Liu, X., Leonid Peshkin, Mihail Barboiu, Stocker, H., Kirschner, M.W. and Basan, M. (2023). Membrane potential as master regulator of cellular mechano-transduction. bioRxiv (Cold Spring Harbor Laboratory). [online] doi:https://doi.org/10.1101/2023.11.02.565386.
Wright, S.H. (2004). Generation of resting membrane potential. Advances in Physiology Education, 28(4), pp.139–142. doi:https://doi.org/10.1152/advan.00029.2004.