Divyan Bavan
Introduction
Excitable cells in the body utilize electrical signalling for rapid communication. The base signal, called an action potential (AP), starts through a depolarization of the cell membrane. This is followed by subsequent repolarization. This structure enables APs to travel along electrically connected cells, establishing cellular circuitry within the body. The specific cells that use APs—neurons, ventricular myocytes, and sinoatrial (SA) nodal cells—utilize them for different purposes. Thus, the exact structure of an AP varies significantly; it is suited for the specific function it holds in its corresponding cell. The primary effectors for these differences are ion channels. Differences in channel expression lead to different ion permeabilities, creating a specific AP structure. By understanding how ion channels influence AP shape in excitable cells, it is possible to understand how molecular mechanisms influence physiological functions.
Action Potentials in Neurons
APs in neurons are triggered by a depolarization of the cell membrane. This is caused by changes in the environment or input from other neurons. These stimuli lead to the opening of specific ion channels. For example, Piezo2 is an ion channel which opens in response to mechanical force. When this channel opens, it leads to an influx of cations—mainly Na+—which causes depolarization. A similar process occurs in neuronal communication. When acetylcholine is used as a neurotransmitter, it binds to nAChR at the postsynaptic neuron. This leads to the channel opening, enabling cations to pass through. This depolarizes the neuron.
If the membrane potential depolarizes past a threshold, voltage-gated sodium channels (Nav) have a high probability of opening. These channels, through conformational changes in their S4 transmembrane domain (TMD), open in response to depolarization of the cell membrane (Alberts et al., 2022). This enables an influx of sodium ions into the cell. The effect of this is further depolarization, opening more Nav channels and leading to further depolarization. This creates a rapid upstroke in the membrane potential, often lasting less than a millisecond. Furthermore, the inactivity of repolarizing ion channels at this stage of the AP means the membrane potential becomes very depolarized; it often reaches about +35mV (Chen et al., 2023).
Once the AP reaches its peak, the neuron must reset the membrane potential. This is mediated through two mechanisms: potassium efflux and Nav inactivation. While depolarization activates Nav channels, it also activates voltage gated potassium channels (Kv). Potassium is responsible for repolarizing the membrane; its efflux from the cell lowers the membrane potential. This process does not interfere with depolarization as Kv channels are delayed rectifiers—they open 1ms later than Nav channels (Grider et al., 2023). However, once the membrane is ready to be reset, the influx of sodium must be stopped. This is done by inactivating Nav. These channels have inactivation gates which also respond to depolarization. Like Kv channels, this gate is delayed; Nav activates, facilitates sodium influx, and then inactivates. These two features are responsible for the repolarization phase.
Kv channels don’t stop once the membrane returns to resting potential, however. Once repolarization occurs, Kv also has an inactivation gate. While this enables potassium efflux to stop, the membrane becomes hyperpolarized before full inactivation. This is then reversed through the sodium potassium pump, bringing the neuron back to resting potential. This entire process takes about 10ms.
Action Potentials in the Sinoatrial Node
Due to their role in processing, neuronal APs have an incentive to be rapid. This is not true for all cells. For example, take the sinoatrial (SA) node. These cells are responsible for setting the steady rhythm of the heart. While this means they shouldn’t be rapid, it does necessitate a unique feature: pacemaker activity. The SA node must generate action potentials spontaneously.
This relies on the funny current (If). If is carried by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels: a cation channel which activates in response to hyperpolarization. When these channels are activated, the membrane becomes depolarized. This is designated as phase 4 of the SA nodal AP. The depolarization is slow until it reaches -35mV (Koeppen and Stanton, 2017). At this point, T-type and L-type calcium channels open. This initiates the phase 0 upstroke. The upstrokes produced by SA nodal cells is much less steep than those produced by neurons, as the latter relies on faster sodium channels. When the peak of the AP is reached, the L-type calcium channels inactivate and delayed rectifier K+ channels open. The two subtypes of these channels are Kr and Ks. The currents produced by these channels, iKr and iKs, lead to the efflux of K+ from the cell. This repolarizes the membrane (phase 3). Once the SA nodal cells reach a membrane potential of below -60mV, the potassium channels close and HCN channels activate. This restarts the cycle, setting the firing rate for the myocardium (Koeppen and Stanton, 2017; Klabunde, 2021).
In instances where this rate must be changed, several messengers can act on SA nodal cells. For example, acetylcholine from the vagus nerve can bind to M2 receptors. This GPCR is associated with a Gi subunit, downregulating cAMP production. The effect of this is less activation of HCN channels and thus, a lower heart rate (Klabunde, 2021). This can also work in the opposite direction. Adrenaline is responsible for increasing heart rate. This happens through the β1 receptor. When adrenaline binds to β1, the receptor activates a Gs subunit. This stimulates the production of cAMP. By binding to the HCN channel, cAMP leads to faster depolarization during phase 4. This increases heart rate (Klabunde, 2021). While this is beneficial when stimulation is needed, several diseases can lead to tachycardia: a chronic increase in heart rate. One cause of this is pheochromocytoma, a tumor on the adrenal medulla which causes excess adrenaline secretion (Gupta et al., 2024). Therefore, it is evident that ion channels in the SA node not only generate cardiac APs, but also modulate them.
Action Potentials in Ventricular Myocytes
After APs are generated in the SA node, they travel through the atria, AV node, and into the ventricular myocytes. These cells have a resting membrane potential (RMP) of -90mV, defined as phase 4. The RMP is very negative to prevent spurious depolarizations from causing APs. The myocardium must contract according to a well-defined cycle, and spurious APs would disrupt that cycle. It is only when an abrupt depolarization to -65mV—caused by the electrical propagation of APs from the SA node—that the ventricular myocytes generate an action potential. The upstroke (phase 0) from the threshold is similar to neurons; it is generated by fast Nav channels. These channels inactivate in about 1-2ms (Koeppen and Stanton, 2017).
At this point in the cycle, the shape of the AP depends on where the ventricular myocyte is located. In the epicardial and midmyocardial regions of the left ventricle, there is a small repolarization (phase 1 notch) caused by transient outward channels. The current (ito) is mainly carried by potassium ions. However, since ito channels are less prominent in the endocardial region of the left ventricle, these cells do not have a notch (Koeppen and Stanton, 2017).
Whether or not a notch is present, a plateau forms quickly after depolarization (phase 2). This is caused by two competing currents. The first is formed by an influx of calcium through L-type calcium channels. While these are activated by depolarization, they activate much more slowly than Nav. The reason why these channels cause a plateau instead of further depolarization is due to the competing potassium currents: ito, iK, and iK1. The first two channels allow the efflux of potassium from the cell, balancing the influx of calcium (Koeppen and Stanton, 2017). This maintains the membrane potential at a plateau.
When the calcium channels inactivate, however, the membrane potential beings to repolarize (phase 3). This is because the potassium channels are still open. Furthermore, once repolarization initiates, iK1 channels open. This accelerates the rate of repolarization. This continues until the myocyte reaches its RMP (Koeppen and Stanton, 2017).
The timeframe for ventricular myocytes and SA nodal cells is heavily extended compared to neurons, as shown in Figure 1. This is due to the reliance of cardiac APs on slow calcium channels. This is beneficial for these cells, however, due to two reasons. The first is that calcium is required for the contractile mechanisms of myocytes. Finally, APs in cardiac cells require controlled pulses rather than short bursts. This is how ion channels directly control not just action potentials, but cell physiology as whole.
Conclusion
It is evident that ion channel diversity plays a critical role in determining the shape of an action potential. In neurons, the speed of Nav and Kv channels enable extremely fast depolarization and repolarization. This aids in the nervous system’s requirement for rapid communication. On the other hand, the SA node has special HCN channels that enable pacemaker activity. They also rely heavily on calcium channels for a slower, controlled upstroke. Ventricular myocytes also rely on calcium channels, not just for the control of the cardiac cycle, but also contraction. This illustrates how ion channels can shape the physiology of entire cells. By further classifying and understanding the diversity of ion channels, we can not only expand our knowledge of physiology, but also better understand how diseases can be treated.
Works Cited
Alberts, Bruce, et al. Molecular Biology of the Cell. 7th ed., New York, W. W. Norton & Company, 2022.
Chen, Isaac, and Forshing Lui. “Neuroanatomy, Neuron Action Potential.” Nih.gov, StatPearls Publishing, 14 Aug. 2023, www.ncbi.nlm.nih.gov/books/NBK546639/.
Grider, Michael H, et al. “Physiology, Action Potential.” National Library of Medicine, StatPearls Publishing, 2023, www.ncbi.nlm.nih.gov/books/NBK538143/.
Gupta, Puneet K., and Bharat Marwaha. “Pheochromocytoma.” PubMed, StatPearls Publishing, 5 Mar. 2023, www.ncbi.nlm.nih.gov/books/NBK589700/.
Klabunde, Richard E. Cardiovascular Physiology Concepts. 3rd ed., New York, Wolters Kluwer Medical, 2021.
Koeppen, Bruce M, and Bruce A Stanton. Berne and Levy Physiology. 7th ed., Saintt Louis Elsevier Health Sciences, 2017.