Divyan Bavan
As organisms become larger, they need a way to rapidly communicate signals across their bodies. In most animals, this is achieved by electrical signals called action potentials (APs). APs are initiated by the depolarization of the cell membrane, and once they pass a threshold potential, a positive feedback loop is created which leads to further depolarization. This process is found in many cells, with the most famous being neurons. In these cells, the AP travels through an axon and into the synaptic terminal, where the action potential is transmitted into another neuron or an effector cell. This entire process is dictated by the movement and activity of ions, ion channels, and receptors. It is only by understanding these components’ roles in generating and propagating action potentials that one can truly appreciate the complexity of the nervous system.
APs can be created by stimuli from the environment or other neurons. The former is detected by specialized receptors for the environmental cue. These receptors are gated ion channels; they only open in response to stimuli like temperature, vibrations, pressure, etc. (Koeppen and Stanton, 2017). Once these channels are open, they increase the permeability of the cell membrane to sodium ions. A similar process occurs in interneurons. When a presynaptic neuron releases excitatory neurotransmitters, they will travel across the synapse and bind to receptors on the postsynaptic neuron. These receptors can be ionic or metabotropic, which can both lead to the opening of sodium channels (Alberts et al., 2022). The reason why the opening of sodium channels is significant is because they depolarize the cell membrane. Depolarization causes the membrane potential to become more positive, moving away from its resting potential—about -70mV in neurons. The resting potential exists because of sodium and potassium gradients. While potassium gradients can be equilibrated by leak channels present in the membrane, sodium mostly cannot (Chrysafides et al., 2023). This leads to an excess of positive charge on the extracellular surface of the membrane, leading to a negatively charged inner membrane. However, once stimuli cause sodium channels to open, the membrane becomes less polarized due to sodium counteracting the negative potential. This leads to a more positively charged inner membrane.
The generation of an AP is dependent on this depolarization. As more sodium channels are opened, the depolarization gets stronger and the membrane potential becomes more positive. This continues until the potential passes a threshold—usually around -55mV. At this potential, voltage-gated sodium channels are activated. These channels operate by sensing changes in the membrane potential, specifically through their S4 transmembrane domain. This domain contains several positively charged arginine residues. When the cell is at its resting membrane potential, it is more favourable for the arginine residues to face the intracellular environment. This conformation blocks sodium ions from passing through. However, as the cell becomes depolarized, these residues change conformation. This causes the ion channel to open, allowing more sodium ions to flow in (Alberts et al., 2022). The result of this is a positive feedback loop; as more sodium ions enter and depolarize the cell, more voltage-gated sodium channels open, which leads to more sodium ion influx. The result of this is the cell’s membrane potential rapidly moving towards sodium’s equilibrium potential of +65mV. This process occurs primarily at the axon initial segment, which is the starting point for APs (Grider et al., 2023).
Now that the AP has been generated, it must be propagated along the axon of the neuron. This is important as APs must reach other neurons and effector cells to relay their encoded signals. Axons have several features to facilitate this process. The first feature is the resting membrane potential, which utilizes charge differences to propagate the AP. An AP leads to a positive membrane potential in the axon hillock, while the rest of the axon has a negative membrane potential. Since ions follow their electrochemical gradient, the current will move along the axon (Byrne et al., 2023). However, there is a problem with this mechanism; as ions move along their electrochemical gradient, the signal gets weaker due to internal resistance. To counteract this, axons have voltage-gated sodium channels (VGSCs) which regenerate the AP. This allows the AP to be properly propagated along the axon. Together, these properties contribute heavily to the propagation speed of the axon (Koeppen and Stanton, 2017). The propagation speed is important as it determines how quickly organisms can respond to stimuli. There are two metrics which can be used to measure it—the time constant and length constant. The former is defined by how fast the axon can generate an AP; the latter is defined by how far that AP can spread along the axon. Therefore, a smaller time constant and larger length constant lead to a faster propagation speed (Byrne et al., 2023; Koeppen and Stanton, 2017). Organisms, in search of faster signaling, can optimize these metrics to enhance efficiency. One strategy is to increase the diameter of the axon. This effectively reduces the internal resistance of the axon, increasing the length constant (Koeppen and Stanton, 2017). The giant squid axon, which Hodgkin and Huxley used to study APs, uses this strategy to increase propagation speed. The next strategy that axons use is to cluster VGSCs in nodes along the axon. Some axons have lipid rafts of voltage-gated sodium channels. This increases the speed at which the action potentials can travel, as clustering the channels speeds up depolarization and travel across the axon (Grider et al., 2023). Some axons take this even further with myelination. Instead of lipid rafts to cluster sodium channels, these axons have a more developed coating called myelin. Myelin is formed by wrapping glial cells such as Schwann cells around an axon. The lipid-dense nature of the cell membranes makes myelin an effective insulator for axons; it causes the resistance of the axon to increase, and thus, less current leaks out (Koeppen and Stanton, 2017). This increases the length constant. The myelin also creates a larger separation of charge across the membrane. This decreases the capacitance and allows the membrane to depolarize faster. Finally, the gaps in between Schwann cells—known as nodes of Ranvier—function similarly to the lipid rafts in unmyelinated axons. VGSCs are clustered in these nodes, allowing faster propagation. These properties all contribute to the much faster conduction velocity in myelinated axons—about 50m/s compared to less than 2m/s in unmyelinated axons (Koeppen and Stanton, 2017).
While speed is important, it is also essential to reset the membrane. This allows an AP to be fired again. The first step of this process is the opening of voltage-gated potassium channels (VGPCs). These channels open in response to depolarization. This results in potassium ions leaving the cell, lowering the membrane potential. The reason why this doesn’t interfere with the rising stage of the action potential is because VGPCs open 1ms more slowly compared to VGSCs. Thus, VGPCs are known as the delayed rectifiers (Bear et al., 2020). The next step for resetting the axon is closing the sodium channels, which happens through two mechanisms. The first is triggering the inactivation gate in the VGSCs. Once the membrane has become depolarized, these inactivation gates close the sodium channels. This prevents further sodium ions from entering the axon, creating the absolute refractory period. This is when the neuron cannot fire another action potential, no matter how much stimulus it receives (Koeppen and Stanton, 2017). Furthermore, by lowering the membrane potential, the probability of opening sodium channels becomes lower. This is the second mechanism (Koeppen and Stanton, 2017). As all three of these processes work together to repolarize the membrane, the potential eventually goes back down to rest. However, VGPCs only close past the resting membrane potential, which means they will continue pumping potassium once it has been reached. This is what causes hyperpolarization: when the membrane goes below its resting potential. The result of this is the relative refractory period; since the membrane’s potential is further away from the threshold, it requires a stronger stimulus to fire another action potential. Eventually, this hyperpolarization is also restored. This is done by the potassium leak channels and the sodium-potassium pump, which restore the resting gradients (Koeppen and Stanton, 2017).
Once the membrane potential is restored, the neuron is ready to fire another AP. This simple cycle of stimulus reception, depolarization, propagation, and repolarization is fundamental to our body’s signaling capabilities. With the sheer number of neurons in the body, it is easy to imagine the magnitude of APs that are fired every second. It is only through our understanding of the ionic mechanisms behind APs that we can fully comprehend how complex these signals are. Understanding these processes has unlocked many new areas of research. For example, multiple sclerosis is caused by the immune system attacking the myelin sheath of myelinated axons. This decreases the efficiency of the affected neurons, causing the disease’s associated symptoms. It is only by understanding the molecular mechanics of APs that we can fully understand the disease. For this reason, scientists are continuing to explore the complexities of APs in hope of finding explanations for other diseases.
Works Cited
Alberts, Bruce, et al. Molecular Biology of the Cell. 7th ed., New York, Garland, 2002.
Bear, Mark. NEUROSCIENCE : Exploring the Brain. 4th ed., S.L., Jones & Bartlett Learning, 2016.
Byrne, John. “Propagation of the Action Potential (Section 1, Chapter 3) Neuroscience Online: An Electronic Textbook for the Neurosciences | Department of Neurobiology and Anatomy - the University of Texas Medical School at Houston.” Nba.uth.tmc.edu, 2023, nba.uth.tmc.edu/neuroscience/s1/chapter03.html.
Chrysafides, Steven M, and Sandeep Sharma. “Physiology, Resting Potential.” National Library of Medicine, StatPearls Publishing, 12 Feb. 2019, www.ncbi.nlm.nih.gov/books/NBK538338/.
Grider, Michael H, et al. “Physiology, Action Potential.” National Library of Medicine, StatPearls Publishing, 2023, www.ncbi.nlm.nih.gov/books/NBK538143/.
Koeppen, Bruce M, and Bruce A Stanton. Berne and Levy Physiology. 7th ed., Saintt Louis Elsevier Health Sciences, 2017.