Dr. Frank-Chris Schoebel
Dr. Frank-Chris Schoebel
Dr. Frank-Chris Schoebel has been working as a cardiologist in Düsseldorf for 25 years and was a member of staff at the Clinic for Cardiology, Pneumology and Angiology at the University Hospital Düsseldorf for more than 16 years, including 6 years as senior physician. To the profile.

Neurotransmitters - Dopamine, Norepinephrine & Serotonin



Metabolic pathways of activating neurotransmitter - a simple model.

In the Cardiopraxis we are increasingly concerned with the metabolic pathways of the activating neurotransmitters dopamine, noradrenaline, serotonin and adrenaline. These not only have an influence on your emotional state and behavior, but also on the cardiovascular system, such as blood pressure and heart rhythm.

To better understand the action of activating neurotransmitters, we need to look at the principles of their metabolism.



Neurotransmitters are messenger substances for signal transmission

Neurotransmitters are messenger substances that convey a message, either between 2 nerves or between a nerve and an end organ, e.g. the heart. In short, neurotransmitters serve the communication, above all in the brain, the main place of information processing for external influences of the environment. In addition, they are also signal transmitters between the brain and the other parts of the body, partly via the autonomic nervous system.

In most cases, several metabolic steps are necessary for the formation of activating neurotransmitters from one amino acid each. For example, we take in the amino acid L-phenylalanine with food and from it the neurotransmitter dopamine is formed through various conversion processes. Since the activating neurotransmitters contain only one amino acid, we consequently also call them monoamines.


Metabolism of neurotransmitters - a simple model

If we look at the metabolism of activating neurotransmitters, we can basically distinguish 4 levels:

  • Education
  • Effect
  • Storage
  • Dismantling

Various factors are involved in these processes. In simplified terms, they are:

  • Nutrients
  • Gene
  • epigenetic factors
  • Enzymes
  • Enzyme co-factors
  • Receptors

All processes and their factors must be in balance for you to be healthy and efficient.

Enzymes and co-factors

Enzymes ensure that neurotransmitters are formed, usually via several metabolic steps. These enzymes are large-molecule proteins that act as catalysts to significantly accelerate the formation process without themselves undergoing any structural or functional changes. Once an enzyme has completed a metabolic step, it is available again for renewed metabolic activity, as long as the right cofactors are present.

Enzymes usually require one or more co-factors to function properly. Although these co-factors are specific to the individual enzyme, they can be quite different for different enzymes. They often come from the group of so-called micronutrients; the best known are vitamins and minerals, such as vitamin B6 or magnesium.

For every enzyme there is one or more optimal co-factors. Or, to put it another way, there is a suitable key for every lock. Only together with the optimal co-factor can the individual enzyme carry out the specific metabolic step at maximum speed.

Now there are also non-optimal co-factors that can slow down or even block a metabolic step. Optimal and non-optimal co-factors compete for the binding site on the enzyme. For example, the optimal co-factor magnesium may be displaced by the non-optimal co-factor calcium.


Enzymes - co-factors as a regulating factor

In a cell, the same type of enzyme occurs several times, since a single enzyme alone could not provide the necessary synthesis performance. In addition to substrate concentration and temperature, the equilibrium between the following states of enzymes is also important for the speed of a metabolic step:

  • unoccupied enzymes without cofactor
  • Enzymes with optimal co-factor
  • Enzymes with non-optimal co-factor

Thus, optimal and non-optimal co-factors compete for the binding site at several enzymes of one type. Depending on how these co-factors, optimal and non-optimal, are in quantitative balance with each other, the metabolic pathway of all enzymes of the same type runs faster or slower in total. In other words, if there are many non-optimal co-factors, the metabolic step runs slowly, if there are many optimal co-factors, it runs faster.

From this it is clear that co-factors have an important regulatory function for metabolic pathways. These relationships have considerable significance against the background of uncontrolled intake of over-the-counter dietary supplements. If the balance is disturbed, either by a preponderance of non-optimal but also of optimal co-factors of an enzyme, then negative health consequences can occur.

We know this very well from Praxis , e.g. from the excessive supply of vitamin B6 (conversion of L-dopa to dopamine by L-aminodecarboxylase). Not only can overtreatment with vitamin B6 result in severe neurological disorders, but it also causes excessive metabolic activity, which in part is mediated by neurotransmitters and leads to inner restlessness, irritability, sleep disorders, sweating and circulatory problems.

Genes and epigenetic factors control the formation of enzymes

Enzymes, as proteins, are themselves formed by a single gene or several genes. Specific genes are located in the nucleus of a cell and are, as it were, pattern templates for the formation of enzymes.

Genes can be switched on and off in their function. The factors that cause this are, among others, "epigenetic factors". In simplified terms, epigenetics means "at the gene. Similar to the co-factors in enzymes, they thus have a regulating function.

Epigenetics is a relatively new field of science. In tumor research in particular, intensive research is being conducted here into epigenetic factors influencing both the formation and the treatment of tumor diseases.

In the regulation of the cardiovascular system by activating neurotransmitters, epigenetic influencing variables also play an important role. According to our experience in connection with systematic scientific findings, e.g. vitamin D and the sex hormones estrogen and testosterone have an importance to be emphasized here.

Vitamin D induces the formation of the enzyme tyrosine hydroxylase (conversion of tyrosine to L-dopa). Testosterone genetically induces increased formation of catechol-O-methytransferase (COMT) and monoaminooxidase (MAO), which in turn is associated with accelerated degradation of activating neurotransmitters. Estrogen, on the other hand, slows down the degradation of activating neurotransmitters via reduced synthesis of COMT and MAO.

You can certainly imagine that these connections have a powerful significance not only for your emotionally controlled behavior, but also for the regulation of the cardiovascular system.

Neurotransmitter signal strength

Once the activating neurotransmitters have been formed, they are released by a signal in the nerve from the transmitter cell into the intercellular space, the so-called synaptic cleft, to transmit the signal to a receiver cell. At the receiver cell, receptors are located in the cell membrane to which the neurotransmitters dock. The receptors then activate further signaling pathways within the target cell.

Several factors are important for the signal strength and whether a signal transmission occurs at all:

  • Signal-sending nerves
  • Neurotransmitter
  • Signal receiving nerves
  • Specific receptors for neurotransmitters

A signal by a signal-sending nerve always involves the release of several neurotransmitters. First of all, the presence of signal-receiving nerves plays a role for the emergence of a signal: no signal transmission without a receiver.

Since whole bundles of nerves are usually responsible for the formation or transmission of a certain signal quality, the numerical ratio of transmitting and receiving nerves also plays a role, whereby several transmitters can also dock with one receiver

Furthermore, the quantitative ratio of neurotransmitters to their specific receptors is also important. For example, despite numerous neurotransmitters in the synaptic cleft, a signal cannot be transmitted if there are few or no receptors on the signal-receiving side.


Receptors for neurotransmitters

When an activating neurotransmitter is released by a signal from the signal-sending nerve, it is initially located in the space between two nerves, the so-called synaptic cleft. It then docks, according to the lock-and-key principle, to specific receptors on the signal-receiving cell. The receptor then triggers an intracellular signal chain in the signal-receiving cell and the signal is then transmitted in the nerve.

Receptors are themselves formed by genes and are themselves regulated by specific epigenetic factors and partly by receptor-specific co-factors. Further regulatory possibilities are the responsiveness of receptors and receptor blockade.

If a receptor mediated by a neurotransmitter has transmitted a signal into the signal-receiving cell, then it is inactive for a certain time afterwards, i.e. it is not available for a renewed signal transmission. If the transmitted signal of all signal-transmitting nerves was quantitatively very strong, then in the sense of exhaustion the whole signal pathway may be blocked for a certain time. Consequently, further signals by the signal-sending nerve remain ineffective.

Blockade of neurotransmitter receptors as a therapeutic principle

Neurotransmitter and receptor are specifically optimally suited to each other in the sense of the lock-and-key principle. Similar to the co-factors of enzymes, however, a non-optimally matching substance can block the receptor for the optimally matching neurotransmitter and thus the effect of the same. This blockade can be competitive, meaning that signal transduction is determined by the quantitative ratio of optimally-acting neurotransmitters to blocking substances. However, there is also non-competitive inhibition, in which the receptor is irreversibly blocked, which in a way corresponds to intoxication.

In cardiovascular medicine, the principle of competitive receptor blockade is regularly used, for example, in therapy with beta-receptor blockers for the treatment of high blood pressure and cardiac arrhythmias. If the beta receptors on the heart are occupied, then norepinephrine and epinephrine cannot develop their full effect on the heart with an increase in heart rate and pumping force.

By the way, we can observe the competitive inhibition by the beta-receptor blocker very nicely in stress echocardiography. People on beta-blocker therapy initially show sluggish pumping at rest. With increasing stress, and thus adrenergic activation, norepinephrine and epinephrine gain the upper hand in the myocardial cells and the pumping force increases significantly; sometimes the examiner has the impression that a switch has been flipped.

Neurotransmitter reuptake

Once a neurotransmitter has fulfilled its function at the receptor of the signal-receiving nerve, it dissolves again so that it is initially free in the space between the signal-receiving and signal-sending nerves, the so-called synaptic cleft. In individual cases, enzymes are found on the outside of the cell membranes, the outer cell boundary here, which cause the degradation of the neurotransmitter.

In most cases, however, the free neurotransmitters are reuptaken into the signal-sending nerve via a reuptake channel. Reuptake channels are protein structures that are also formed on the basis of genes. Thus, due to genetic variants, the reuptake of neurotransmitters can differ from person to person: one person's reuptake is faster, another's slower.

The function of reuptake channels is also used therapeutically for activating neurotransmitters. Thus, in the treatment of depression, we use the so-called serotonin or norepinephrine reuptake inhibitors. By blocking reuptake, the concentration of the neurotransmitter in the synaptic cleft is increased and the effect on the signal-receiving nerve is enhanced.

If the neurotransmitters are reabsorbed into the signal-sending nerve via the reuptake channel, then they are either stored or degraded.

Neurotransmitter storage

As a rule, the signal-sending nerve stores the neurotransmitters after their reuptake. This occurs in small storage vesicles, so-called storage vesicles. To enter a storage vesicle, the neurotransmitter must again pass through a transporter channel, which also consists of proteins. The transporter, usually the vesicular monoamine transporter 2 (VMAT2), is the same for all activating neurotransmitters (dopamine, norepinephrine, epinephrine and serotonin).

In the vesicles, the neurotransmitters are protected from the degrading enzymes that are located inside the cell but outside the vesicles. If the signal-sending nerve is activated again, the neurotransmitters in the vesicles are available for renewed signal transmission to the signal-receiving nerve.

We also use the function of a vesicle transporter therapeutically. The blockade of the transporter VMAT2, e.g. by reserpine can be used therapeutically in case of excessive neurovegetative activation, e.g. for the treatment of hypertension or in case of inner restlessness and anxiety. In short, reserpine blocks the uptake of activating neurotransmitters into protective vesicles. Consequently, enzymes then increasingly break down the neurotransmitters outside the vesicles.

Degradation of neurotransmitters

The degradation of activating neurotransmitters occurs predominantly within the signal-sending nerve. Just as in the formation of neurotransmitters, enzymes play a decisive role in their degradation. Again, activity, genes and co-factors are of regulating importance.

Of particular importance here are the enzymes catechol-O-methytransferase (COMT) and monoamine oxidases (MAO). We know genetic variants for COMT and MAO. In humans, for example, there are genetically determined high, medium and low degradation rates of activating neurotransmitters by COMT and MAO, respectively. If the degradation rate is low, for example, then the neurotransmitters "pile up" in front of the enzyme and this person tends to have an increased activity level. If the degradation rate is high, then the activity level is rather low.

In terms of human behavior, this means higher or lower irritability and thus also partly explains the different temperaments between individual people. Especially the genetic variants of COMT and MAO are extensively studied in behavioral research. For example, low activity of COMT with a "congestion" of dopamine and norepinephrine can help explain inner restlessness and a tendency to panic attacks. Increased activity of MAO and the associated increased rate of degradation of the neurotransmitter serotonin may predispose to depression.

Activating neurotransmitters - targeted therapeutic use of genetic correlations

Knowledge of genetic differences in the build-up and breakdown of activating neurotransmitters is a very good option for better individualization of therapeutic measures in cardiovascular medicine.

Especially in the treatment of cardiac arrhythmias and hypertension, which are not only dependent on disturbances of the organ heart or the blood vessels themselves, the knowledge of the individual genetic prerequisite for the effect of activating neurotransmitters has an increasing therapeutic importance. Not only does this make it easier to explain behavioral patterns, but it also enables us to make more specific recommendations for drug therapy, the use of nutritional supplements and the effects of hormone preparations, be they estrogen, progesterone or testosterone. These in turn have an effect on the heart and circulation.


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