In the previous article, we looked at the process by which neurons generate action potentials and transmit signals. We noted that for a given stimulus to successfully trigger an action potential, it must reach a threshold value, which represents the minimum amount of stimulation required. Furthermore, we observed that even if the stimulus is extremely large, the amplitude of the action potential does not
exceed +40 mV, as the size of the action potential remains consistent. Instead, in such cases, multiple action potentials occur rapidly in succession. Now, let’s explore the magnitude of these stimuli in more detail.A single neuron can form hundreds or tens of thousands of synapses.
In the previous article, the diagram of a neuron, created with my limited PowerPoint skills, shows one neuron connected to another neuron by a synapse. However, this was only intended to make it easier to understand; in reality, a single neuron is connected to hundreds of synapses. Multiple neurons transmit various signals to a single neuron simultaneously, influencing it. The reason dendrites extend like the branches of a tree in many directions is likely to allow connections with many neurons and synapses at the same time.
Here, let's briefly revisit the role and mechanism of action of neurotransmitters. In signal transmission between neurons, they do not physically touch each other. Instead, there is a very small gap known as the synaptic cleft between them, and as the electrical signal crosses this gap, it is converted into a chemical signal called a neurotransmitter. When the voltage reaches the end of the axon terminal of the presynaptic neuron, it triggers the opening of voltage-gated calcium channels, allowing Ca+2 ions to flow into the cell. This influx of calcium causes the neurotransmitters that have already been produced and stored to be pushed into the synaptic space outside. The neurotransmitter that corresponds to the content being transmitted as an electrical signal is released, continuing the relay of the signal. This narrow synaptic space, measuring just 20 nanometers (20 x 10-9 meters), is filled with extracellular fluid, allowing the released neurotransmitters to move toward the postsynaptic neuron's dendrites and bind to the receptors on its cell membrane. This process is known as ligand binding. The signal has crossed the river called synapse.
Which receptor will neurotransmitters bind to in the postsynaptic neuron?
There are currently hundreds of known neurotransmitters, and new ones continue to be discovered. The specific receptor that a neurotransmitter binds to varies greatly depending on the function of that neurotransmitter. For example, if the electrical signal being transmitted contains a command for the skeletal muscle to contract, then when this electrical signal reaches the terminal of the presynaptic neuron, it must release the excitatory neurotransmitter, acetylcholine, to continue the signal to the postsynaptic neuron. The neurotransmitter that has crossed the synaptic cleft will bind to ligands on the postsynaptic neuron, opening various ion channels, which is a very important process. The specific ion channels that open will ultimately determine whether a localized voltage is generated near the cell membrane of the postsynaptic neuron, which directly affects whether an action potential can be created to continue the signal.
Excitatory neurotransmitters aim to generate action potentials and continue the signal.
Let’s continue to focus on acetylcholine. If the goal of acetylcholine is to contract muscles, then the postsynaptic neuron must maintain action potentials to excite the muscles and facilitate contraction. This means that the chemical signal must be converted back into an electrical signal. Returning to the process of action potential generation, to create an electrical spike, the membrane potential must first be reversed beyond the threshold. Therefore, Na+ ions must come in to raise the resting membrane's negative charge to a positive charge, and for this to happen, Na+ ion channels must open. Thus, it is easy to infer that the neurotransmitter acetylcholine must bind to receptors that open Na+ ion channels. When Na+ ions flow in through these fully opened channels, the postsynaptic neuron’s membrane, initially in a resting polarized state, begins to depolarize. The localized voltage temporarily generated by these excitatory neurotransmitters is called excitatory postsynaptic potential (EPSP). EPSP is a potential that increases the likelihood of generating an action potential.
The excitatory postsynaptic potentials (EPSPs) generated at the postsynaptic neuron's membrane are, in themselves, quite small and are likely to dissipate naturally during their transmission from the membrane to the cell body. As mentioned earlier, action potentials begin at the axon hillock, meaning that if the EPSPs do not reach this point, they will fade away. However, if other presynaptic neurons generate EPSPs simultaneously, these can combine to create a sufficient positive voltage, allowing depolarization to the threshold of -55 mV. This means that the postsynaptic neuron is now prepared to fire an action potential. The electrical signal that reached the terminal of the presynaptic neuron transformed into a chemical signal in the form of neurotransmitters, and then returned to an electrical signal in the postsynaptic neuron, continuing the relay of the signal. For this reason, the transmission of signals in the nervous system is referred to as "electrochemical coupling." When the EPSPs generated by one or more presynaptic neurons combine and add together to reach sufficient threshold levels, this is known as action potential generation through spatial summation.
Inhibitory neurotransmitters interfere with action potential generation.
However, while there are excitatory neurotransmitters whose purpose is to generate action potentials, there are also inhibitory neurotransmitters that prevent this process. So, what receptors do these inhibitory neurotransmitters bind to at the postsynaptic neuron's membrane? If they can maintain or even increase the intracellular negative charge of the postsynaptic neuron, they will push the membrane potential in the opposite direction of the threshold, preventing action potential generation. To achieve this, they may open chloride ion (Cl-) channels, making the negative charge stronger, or open potassium (K+) channels, allowing K+ ions to exit the cell due to concentration differences, further increasing the intracellular negativity and causing hyperpolarization. In other words, inhibitory neurotransmitters aim to bind to receptors that open K+ or Cl- ion channels, thereby blocking the opportunity for action potential generation. The voltage difference created by this process is referred to as inhibitory postsynaptic potential (IPSP).
Graded potential: Summation of excitatory/inhibitory neurotransmitters
A single neuron can form thousands of synaptic connections with other neurons, which means that various neurotransmitters can be released simultaneously toward one neuron, resulting in numerous EPSPs and IPSPs being generated at the same time. When all of these are summed up, if the total reaches the threshold, it will lead to an action potential. The more EPSPs there are, the greater the likelihood of reaching the threshold, while a higher number of IPSPs will have the opposite effect. In other words, whether the postsynaptic neuron continues to propagate the signal is determined not by a single neurotransmitter, but by the total amount of all neurotransmitters present. The action potential will depend on whether excitatory or inhibitory neurotransmitters are dominant. If excitatory and inhibitory substances are released in similar amounts simultaneously, they will likely cancel each other out, preventing the generation of an action potential. Conversely, if excitatory neurotransmitters are predominant at a given moment, the signal will continue.
There are two methods of summation: spatial and temporal. Spatial summation occurs when EPSPs generated by multiple presynaptic neurons combine to exceed the threshold voltage. On the other hand, temporal summation occurs when a single neuron releases neurotransmitters repeatedly in very short intervals, generating EPSPs, or when several presynaptic neurons generate EPSPs in quick succession within a very short time frame. These values can also sum up to reach the threshold. As the name suggests, the key aspect of temporal summation is that it must occur within a very short time. If the subsequent EPSP occurs too late, it may weaken and dissipate before it can add to the previous EPSP. Regardless of how the summation occurs, the voltage differences generated at the dendrites must reach the threshold at the axon hillock for an action potential to occur; otherwise, they will dissipate. Remember that EPSPs cause depolarization while IPSPs cause hyperpolarization, so when summing these values, they play roles of + and - respectively.
The process by which neurotransmitters bind to different receptors to create EPSP or IPSP potentials, depending on whether they are excitatory or inhibitory, is referred to as graded potential. This is distinct from action potentials, which are initiated instantaneously by voltage-gated channels.
Degradation and Reuptake of Neurotransmitters
Another important aspect to mention is the degradation of neurotransmitters that are released at the synapse. What happens to the signaling molecules that remain after binding to the receptors of the postsynaptic neuron? If they were to stay in the synapse indefinitely, it would cause significant disruption to the signaling, continuously generating EPSPs or IPSPs. It is only natural that these neurotransmitters should promptly leave the scene once their task is complete. Therefore, there are specific enzymes dedicated to processing all neurotransmitters. Thanks to these enzymes, neurotransmitters function for only a very short period in the body. The enzymes quickly break them down and reabsorb them back into the presynaptic neuron so that they can be recycled when new neurotransmitters are produced in the future.
Additionally, medications can be developed to inhibit the activity of these diligent enzymes for therapeutic purposes. For example, in patients suffering from depression or anxiety disorders, the neurotransmitter serotonin, often referred to as the "happiness hormone," can be made to last longer in the body by targeting and inhibiting the enzymes that break down to reabsorb serotonin. In pharmacology, such medications are classified under the category of selective serotonin reuptake inhibitors (SSRIs). The well-known drug Prozac falls into this category.
Why are inhibitory neurotransmitters Necessary?
Is it just me who wonders if having only excitatory neurotransmitters would be enough for effective signal transmission? If only excitation occurs, fine control becomes almost impossible. For instance, if only excitatory neurotransmitters were released when we grasp an object, we would end up squeezing it too tightly. Therefore, in order to control fine hand movements, an appropriate amount of excitement and inhibition is essential.We can see this in the way that young children's movements are unnatural and clumsy, but become more delicate as they grow. A balance among neurotransmitters is needed for nerves to properly stimulate and transmit signals.
However, perhaps most importantly, inhibitory neurotransmitters allow us to filter the vast amount of information that comes our way, helping us control what to ignore and what to pay attention to. The ability to sleep and to focus on a single task ultimately comes from the brain's capacity to suppress and disregard certain incoming information. When this process malfunctions, it can lead to conditions such as epileptic seizures, which are essentially an overload of electrical signals being transmitted to the brain.
In fact, whether a neurotransmitter is excitatory or inhibitory, and which type is more dominant, is a crucial concept that determines whether signals will continue or dissipate. This is because the hundreds of neurotransmitters present in the human body ultimately represent the activities of the brain that we are familiar with. The precise regulation of various neurotransmitter levels adjusts our behaviors, emotions, and thoughts. The way numerous neurotransmitters act can influence our behaviors and emotional states. All brain activities, such as contracting skeletal and smooth muscles, facilitating learning and memory processes, and regulating sleep, are achieved through the harmonious interplay of different neurotransmitters.
Acetylcholine, a neurotransmitter also involved in memory, has been found to be significantly reduced in patients with dementia. Therefore, one of the current treatments for dementia involves prescribing medications that increase acetylcholine levels. When neurotransmitters are not properly released, signaling between neurons can be disrupted, leading to states of depression, hallucinations, and addiction, making it difficult to maintain a normal and healthy life.
Neurotransmitters and Modern Society.
As mentioned earlier, acetylcholine, which is responsible for muscle contraction, is also involved in memory in relation to dementia. This serves as a good example of the diverse functions that a single neurotransmitter can perform. Given the variety of tasks the brain must handle, this is a natural outcome. Even the same neurotransmitter can bind to different receptors and exhibit entirely opposite functions. For instance, when acetylcholine is released from motor neurons to stimulate skeletal muscle contraction, it binds to nicotinic receptors to cause muscle contraction. In contrast, when it acts on cardiac muscle, it binds to muscarinic receptors to reduce contraction, leading to relaxation of the heart muscle. One enhances contraction while the other decreases it. The signaling pathways followed by these two receptors are also different, which will be discussed separately in a future article on intracellular signaling systems.
Neurotransmitters seem to be becoming increasingly important for individuals living in this modern times. There are growing numbers of people suffering from various cognitive disorders, memory impairments, and motor function disorders, such as Alzheimer's and Parkinson's diseases, with incidence rates increasing and onset ages becoming younger. Additionally, more individuals are struggling with depression and sleep disorders, all of which are reported to be related to either an excess or deficiency of neurotransmitters. Not only that, considering that 30-35% of gluten, a wheat flour protein that has recently been receiving attention, is glutamic acid, and the most representative excitatory neurotransmitter in the body is glutamate amino acid, there is also a suggestion that excessive consumption of wheat flour foods can cause excitatory toxicity in the body and cause neurological diseases. This is an interesting part that requires more detailed examination. Personally, this is an area that interests me along with the relationship between gluten and various autoimmune diseases. I really hope to cover related information again in another article in the future.
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