In the previous article, it was mentioned that excitable cells, such as muscle cells, nerve cells, and some secretory cells, generate electricity to send signals. The ions involved in this process vary slightly, and the mechanisms of electricity generation also differ. In this article, we will explore how neurons generate electricity to transmit signals.
Signals in Neurons: Reporting and Commanding
Two triggering points cause nerve cells, neuron, to generate an electrical impulse called an 'action potential' for the purpose of signal transmission. The first is when the sensory nerves at the terminal detect changes that have occurred outside and inside the body through various receptors, they convert this stimulus into a signal and send it up to the brain via the central nervous system. The second is when the decision or command made by the brain or spinal cord based on the signal received is transmitted to another neuron to reach effectors(such as skeletal muscle) to carry out appropriate responses to external stimuli. In other words, action potentials are initiated through two mechanisms: when ion channels are opened by the sensory receptors in sensory neurons, or when ion channels at post-synaptic neurons are opened through binding with neurotransmitters released by pre-synaptic neurons.
To detect changes in the external and internal environments, we are born with various sensory receptors distributed throughout our bodies. These include olfactory receptors, photoreceptors, temperature receptors, and mechanoreceptors located in the skin, muscles, and internal organs, as well as proprioceptors that allow us to perceive our body's position even with our eyes closed, and nociceptors that detect pain to protect internal organs. These receptors sense minor changes occurring inside and outside the body and report them to the brain.
The signal transmission path to the brain is described in levels, and the peripheral sensory neurons where these sensory receptors are most active are referred to as first-order neurons, representing the lowest level in the signaling pathway. This indicates the initial source of signal transmission. When these sensory receptors detect a slight change or stimulus, they change their structural shape, causing ion channels to open and allowing ions to flow into the cell. As will be discussed in detail below, these ions create changes in the voltage environment around the cell membrane, enabling the generation of action potentials and the transmission of signals.
Let's take a closer look. First-order neurons convert the sensed stimuli into electrical signals known as action potentials and transmit them to the second-order neurons in the spinal cord. These neurons then send the signals to the final stage, which is the third-order neurons in the thalamus of the brain. Here, the signal transmission between different levels occurs through synapses, where neurotransmitters that have passed through the synaptic space open ion channels in the postsynaptic neuron's cell membrane, generating action potentials. At this point, ions again influence the electrical environment of the cell membrane. All activities in the nervous system occur through action potentials. Everything we think, remember, and create is also accomplished through action potentials. The key players in the generation of action potentials are the ions and ion channels.
We have the potential to create voltage.
The inside and outside of living cells exhibit electrical polarity. Specifically, the inside of the cell is relatively much more negatively charged than the outside, creating a polarized state around the cell membrane. This condition is present in all cells; however, only excitable cells utilize this polarized state and the difference in ion concentrations to generate electricity. The already established polarized state holds the energy necessary to create electricity, which means potential. Just like a car filled with gasoline cannot move without a spark from the battery, a change is needed to trigger the reversal of this polarized state. A very brief moment of reversal from negative to positive charge—that is the key. To drive this change in charge, the active participation of charged ions is required. In neurons, sodium (Na+) and potassium (K+) are the main players.
We understand that events occurring at the cellular level happen much more rapidly than one might imagine. A moment divided into one trillionth of a second is referred to as a picosecond, and we often deal with such incredibly short moments. Of course, the voltage generation in neurons occurs over approximately 1 millisecond, producing a small electrical spark of about 100 mV, with a transmission speed of up to around 150 meters per second.[1] While this speed may seem fast, it is actually not very quick compared to the speed of light or the general speed of electrical currents.
Resting Membrane Potential
The voltage of the cell membrane in its polarized state without any applied stimulus, that is, the voltage in the resting state, is called the resting membrane potential, and the voltage that is created by the instantaneous reversal is called the action potential. Personally, the term 'action potential' doesn't quite convey its meaning to me. I can't help but wonder if a more effective term had been used, it might have been a bit easier for someone like me to understand. However, we can evoke the image of water trapped in a dam that falls downward. In this context, though, it seems to relate more to relative differences rather than physical height.
When measuring the voltage of a resting cell with a voltmeter, it is found that the inside of the cell is approximately -70 to -90 mV (millivolts) compared to the outside. This value represents the relative voltage difference between the inside and outside of the cell. While there may be slight variations between cells and individuals, -70 mV is commonly accepted as the resting membrane potential.
Neurons and Synapses
The trigger point for generating electricity in nerve cells is called a "stimulus." Fortunately, cardiac muscle cells can generate electricity without external stimuli (pacemaker cells). Let's imagine that a sensory neuron is activated when something touches the tip of a finger. Unlike other cells that are round or slightly square and plump, neurons often have elongated, stretched-out shapes. This shape is suitable for generating electrical signals sequentially, like a line of dominoes falling, using their thin, long axons. Isn’t it astonishing that a single neuron can have an axon over a meter long? Because of this shape, nerve cells are also referred to as nerve "fibers."
The point where one neuron connects to another is called a synapse. You've probably heard that the more you use your brain, the better your memory becomes and the more your brain's performance improves. This is likely because the increase in brain usage leads to more synaptic connections between the brain and the brainstem, rather than an increase in the number of neurons in the brain. The neuron that sends the signal is called the pre-synaptic neuron, while the neuron that receives the signal is known as the post-synaptic neuron. Although this naming convention is quite obvious, it is a crucial concept. Various neurotransmitters, released from the pre-synaptic neuron, act like small boats crossing the synapse to relay chemical signals to the post-synaptic neuron. The synapse can also be considered part of the extracellular fluid. We will address neurotransmitters again later.
Preview: How to express action potentials in a few lines?
The original resting state of -70 mV is referred to as a polarized state because the inside and outside of the cell are polarized. When a large influx of positive charge occurs, the polarity is rapidly reversed, leading to a depolarized state, which is no longer considered polarized. Subsequently, as cations exit the cell in large quantities, the inside returns to a negative charge, resulting in a repolarized state. During this process, the negative charge dips slightly below the original -70 mV to about -90 mV before returning to its baseline. This point is called the hyperpolarized state. The cycle of polarization - depolarization - hyperpolarization - repolarization continuously repeats, allowing electrical signals to be transmitted. Now that we've looked at the preview, let's move on to the main content.
Generation of Action potentials
Axon hillock: The point of electrical generation
The signals of stimuli and commands traveling between the brain and the peripheral nervous system are transmitted along the axon of the neuron, much like electricity flowing through an electric wire. The cell body (soma) and dendrites receive the stimuli, and when a sufficient amount of stimulation accumulates to generate electricity, voltage begins to form at the axon hillock, the region where the axon starts. In other words, the signal is transmitted away from the cell body toward the end of the axon. When a stimulus is detected, sodium (Na+) ion channels first open.
Sodium (Na+) Ion Channels
Among the various ion channels present in all cell membranes, the only channels that are always slightly open are the potassium (K+) ion channels (leaky channels). The Na+ ion channels are typically tightly closed. Considering both the electrical gradient created by the strong negative ions inside the cell that attract the positively charged Na+ ions, and the chemical gradient where Na+ is distributed at a concentration about ten times higher outside the cell than inside, Na+ would like to enter the cell. However, because the channels are closed, movement does not occur. When a stimulus is applied, it briefly opens the Na+ channels, allowing sodium cations (Na+) to rush into the cell. This causes a change in the electrical polarity within the cell. The resting membrane voltage of the cell is usually around -70 mV, and as the positively charged Na+ enters, the inside of the cell becomes less negatively charged. One could say that the cations dilute the anions.
Threshold: The value to exceed
At this point, the stronger the stimulus, the more Na+ ion channels will open, allowing more Na+ to flow into the cell. Increasing the intensity of sound transmitted to the sensory neurons in the ear or increasing the amount of neurotransmitters secreted to the post-synaptic cell all serve to increase the magnitude of the stimulus. Depending on the size of the stimulus, a corresponding amount of Na+ enters, influencing the electrical polarity. However, if the amount of this stimulus is small and the influx of Na+ is minimal, the stimulus will only cause localized depolarization and will dissipate. It will not lead to a dramatic reversal to a fully positive charge, and the original polarized state will be maintained. In other words, there is a certain threshold that must be surpassed to successfully generate an action potential through a complete reversal of polarity, known as the threshold. Unfortunately, no matter how many stimuli are applied, if their strength is not sufficient to surpass this threshold, nothing happens. This is truly an 'all or none' phenomenon. Such stimuli fade away without producing any effect. Although it may not be exactly same but, one might compare it to a toilet tank that only flushes when the water reaches a certain level; until then, no matter how much the lever is pressed, it will not work and will only waste water.
If there is sound but if the sound level is below the threshold, our sensory neurons cannot recognize it as a stimulus to generate an action potential and send a signal to the brain. In other words, the sound exists, but it is not strong enough for our ears to perceive it. If the light in a room is gradually dimmed to the point of darkness, even though the light exists, it becomes too dark for the photoreceptors in our eyes to respond, leading us to feel that there is no light. Similarly, if a bug is crawling on our body but does not exert enough weight to activate our sensory receptors, we will not sense it. Every nervous system has a threshold. A specific level of stimulation, or threshold, is approximately -50 mV. This threshold is important because the moment the voltage surpasses this threshold (suprathreshold), voltage-gated sodium ion channels begin to open. We have previously examined in detail ligand-gated ion channels, which open when a ligand binds to a receptor, and voltage-gated ion channels, which open at specific voltages, in the article about the membrane protein. Through these channels, a massive influx of Na+ occurs, raising the proportion of positive charge inside the cell and causing a rapid reversal that sparks the action potential. This spark then sends a signal to the brain.
From Depolarization to Repolarization
As soon as the threshold is surpassed, the additional Na+ rushing in through the opened voltage-gated Na+ ion channels quickly raises the intracellular voltage to a positive charge. However, the positive charge of the cell membrane does not continue to rise beyond a certain point. The action potential typically reaches about +40 mV. When this voltage level is approached, the voltage-gated Na+ ion channels begin to close to prevent further influx of Na+. At the same time, the voltage-gated potassium (K+) channels start to open. Why is this? Just like pulling back the rubber band of a slingshot to shoot again, the environment of the cell membrane, which has become positively charged, needs to quickly return to its original negative state. To achieve this, the influx of Na+ cations must be sharply blocked, and K+ channels are opened to allow the high concentration of K+ ions (30 times more) inside the cell to rush out, as they are eager to move to the lower concentration outside the cell. When a large number of cations exit, the inside of the cell becomes relatively negatively charged.
A Brief State of Hyperpolarization
Unlike the Na+ channels that close sharply, the K+ channels, which are always slightly open, cause the charge to drop briefly below the original negative charge. While the sodium channels are precisely controlled to open and close, the potassium channels, like their nickname "leaky channels", cannot prevent the continuous leakage of potassium, leading to a temporary state of hyperpolarization. However, once the membrane potential returns to the original -70 mV, the process of creating sparks for action potentials can be repeated. Of course, if there is no stimulus, it can return to a resting state.
The process described above can be illustrated with the images below.
The Importance of the Refractory Period: Integrity of Signals
When the peak of the action potential is reached, the Na+ channels close completely and remain closed for a while. This is very important because, without the influx of Na+, another action potential cannot be generated. There is no Na+ influx while K+ is being expelled and until the cell returns to the repolarization state. This period when the Na+ channels are closed is called the refractory period. Just like once you’ve pulled back a slingshot and released it, you cannot immediately pull it back and fire again; you need to pull it back once more to launch again. Similarly, after firing an action potential, the Na+ channels must remain firmly closed to quickly return to the original membrane state and prepare to fire the next signal. This is necessary because the membrane potential needs to be polarized back to a negative state. Therefore, the action potential continues to propagate in the direction that is already polarized. In other words, the electrical signal travels in one direction and does not backtrack. The fact that action potentials do not overlap during the refractory period means that signals do not overlap, thus ensuring the integrity of the signals transmitted in one direction.
Sodium Potassium Pump (Na+/K+ ATPase): The Hidden Supporter
To create an environment where action potential can be fired again, the original resting membrane potential of -70 mV must be restored. Without this, there is no environment to generate electrical signals. Therefore, Na+ and K+ must always exist with extreme concentration differences inside and outside the cell. There is one important element that contributes to establishing this concentration difference: the sodium-potassium pump. This pump uses ATP to simultaneously move three Na+ ions out of the cell and two K+ ions into the cell, effectively exchanging them. Thanks to this pump, Na+ can exist at high concentrations outside the cell, while K+ remains at high concentrations inside. It plays a crucial role in pulling K+ back into the cell, especially since K+ tends to leak out. It acts as a reliable backup for the rapid ion concentration regulation that occurs through the opening and closing of ion channels for a very brief moment. The coordinated and perfect control of these ions produces signals. Once again, I am in awe. The more I learn about our body, the more I realize that it has an incredibly sophisticated system.
Action potentials as waves
We have looked at the detailed mechanism by which cells generate voltage to send signals and communicate. Action potentials are like waves that occur sequentially in one direction. It is similar to dominoes falling one after another and passing the effect forward. The difference is that the fallen cell, unlike a domino, quickly stands back up to prepare for the next signal. We constantly generate electricity and send signals. It is proof that we are alive. Dead cells do not have a voltage difference of -70 mV, much like domino pieces that cannot get back up once they fall.
The adult brain contains about 100 billion neurons, and a single neuron can easily connect to thousands of other neurons through synapses.[2] In the case of the heart and skeletal muscles, which are other human organs that operate through action potentials, the ions involved are different, and the duration of the action potential and the duration of the refractory period are also different. For example, simply comparing, in the heart, one action potential corresponds to one heartbeat, which means that the maximum number of action potentials produced in a minute is calculated to be around 200. This is significantly slower compared to nerve cells, which can generate 100 action potentials in just one second. However, what is certain is that all of these cells are engaged in tremendous amounts of electrical activity for the daily functions of life.
In the movie "The Matrix," there is a scene where machines use humans as an energy source, replacing the sun that humans have destroyed. All cells exhibit electrical polarity, and since each cell can generate electricity, it makes me wonder if we might already be a huge living battery. In fact, the world-renowned neuroscientist Dr. Rodolfo R. Llinás also pointed out in his intriguing book that "a neuron is essentially a battery, and like a battery, it can generate a voltage." [3]
[References]
[1] Increased Conduction Velocity as a Result of Myelination
https://www.ncbi.nlm.nih.gov/books/NBK10921/
[2] Understanding neurogenesis in the adult human brain
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4689008/
[3] Rodolfo R. Llinás, i of the Vortex: From Neurons to Self (Bradford Books) by Rodolfo R Llinás (2001-05-01)
