Raul Gainetdinov: Welcome to my talk. I'm happy that you're joining me. My name is Raul Gainetdinov and I would like to present today the history of trace amines and their receptors. I am Director of the Institute of Translational Biomedicine of St. Petersburg State University in Russia. Today, I would like to present the history of trace amines and their receptors. This is my disclosure slide. Trace amines, small and lipophylic substances, such as beta-phenylethylamine, tyramine, tryptamine, and octopamine, structurally and functionally close to classical monoamines. You can see on the right here the structures of them in comparison to classical monoamines.
They're known in fact for more than 130 years. They're termed as false neurotransmitters in mammals because they believe to the acting as modulators of classical neurotransmitters, but in invertebrates, tyramine and octopamine are major neurotransmitters. In fact, octopamine was discovered in octopus, that's how the name octopamine appeared.
They're produced endogenously in our body by decarboxylation of amino acids, and can be metabolized by monoamine oxidase. They also produce exogenously by bacterial decarboxylases from amino acids. They present in foodstuff involving bacterial fermentation, such as cured meats, wine, cheese, but they're also produced by human microbiota and this is very exciting topic. It's absolutely unknown at the moment what trace amines created by human microbiota do in our organism. I expect several interesting studies should appear soon.
The importance of trace amines in psychiatry and pharmacology is difficult to overstate due to, for example, this example. The name of two important compounds in neuropsychopharmacology, such as dopamine and amphetamine appeared in effect from beta-phenylethylamine, the most known and the best characterized trace amine beta-phenylethylamine. In fact, dopamine differed from beta-phenylethylamin just by two OH groups and that's why the full name of dopamine is 3,4-dehydroxyphenylethylamine, abbreviated as dopamine.
Amphetamine differs from beta-phenylethylamin only by one alpha-methyl group and only because of this alpha-methyl group, amphetamine cannot be metabolized by monoamine oxidase. In fact, amphetamine is unmetabolizable but phenylethylamine, or if to say in other words, that phenylethylamine, some researchers consider as endogenous amphetamine, which can be quickly metabolized. That's a major difference between these two compounds.
Trace amines are present at low concentration in the mammalian brain. Normally, they're about 3, 400 times lower than dopamine, serotonin, or norepinephrine, but in fact, the rate of synthesis of trace amines are comparable to dopamine. The reason for such low concentration is probably because it cannot be stored in the vesicles and releases insensitive to depolarization. That is why they're considered as false neurotransmitters.
In fact, beta-phenylethylamine was isolated first in 1876 by a famous Polish researcher, Marceli Nencki from rotten egg white. Marceli Nencki was interested in the mechanisms of decomposition of proteins and discovered this first trace in beta-phenylethylamine. He was working in Switzerland but later, interestingly, he moved to Russia to Institute of Experimental Medicine created by Ivan Pavlof. In this photo on the right, you can see a person in white is Ivan Pavlov, and Marceli Nencki should be here as well, but I'm not sure that I can recommend more other bearded people.
In 2001, a revolution happened in trace amine field when receptors were discovered, specific receptors for trace amines. 9 to 16 GPCR genes from human to rodents were identified. In fact, a number of trace amine associated receptors is different in different species with maximum number 122 found in zebrafish and 0 in dolphines. Humans have nine genes.
All TAARs share common motif. All TAARs are located on a single chromosome. We were invited to write a commentary to this paper to this report. I was working at Duke in the laboratory of Mark Caron at the moment, and we wrote this short commentary following the trace of elusive amines. The journey has started, and the longer we continue to go on this path, the more exciting it becomes.
In fact, companies sign up to corporation who discovered these receptors. They were looking for new serotonin receptors, and it's not surprising, because most likely, TAAR family evolved from a common ancestor gene sharing the closest similarity to 5-HT4 serotonin receptor, but it's clearly different family of receptors, not serotonin receptors.
As I mentioned, nine genes were discovered in humans. They had different names like TA1, GPR58, GPR57, but later, they were renamed as trace amine associated receptors by numbers one to nine and just by order of appearance on chromosome. Three of these genes are not functional. They are pseudo genes. In fact, we have six functional trace amine associated receptors, TAAR 1, TAAR 2, TAAR 5, TAAR 6, TAAR 8, and TAAR 9.
Now, when we realized that we have these receptors which can be activated by tracing it, one interesting feature is emerging. In fact, for every amino acid we have in our body, there is decarboxylated amine. If you take amino acid and cut it apart, you get amine, and looks like majority of these amines, they activate one or another TAAR receptor in one or another species. From ornithine, decarboxylated amine is putrescine. From phenyl, betaphenylamine. From tryptophan, tryptamine. From tyrosine, tyramine. From valine, isobutylamine and so on, and as you can see here, many of them can activate one or another trace amine associated receptor.
The list can be continued and you can see here several more amines and trace amine associated receptor that they can activate. The best studied trace amine associated receptor is TAAR1. TAAR1 is expressed both in the central and peripheral tissues. In the brain, TAAR1 is localized in structures associated with psychiatric disorders, such as ventral tegmental area, dopaminergic region, dorsal raphe neurons, serotonergic region. Prefrontal cortex, glutamatergic region associated with cognitive functions and impulsivity. Peripherally, TAAR1 is localized in the gut and pancreas and can be involved in energy metabolism.
TAAR1 can affect most important neurotransmitters involved in psychiatric disorders. TAAR1 modulates dopamine system. As I mentioned, TAAR1 is expressed in ventral tegmental area and also in substantia nigra. TAAR1 agonism provides a new way to block hyperactive dopaminergic system. If one would increase TAAR1 activity, it can decrease dopamine neurotransmission and vice versa.
If one would block TAAR1 activity, dopamine transmission is enhanced. TAAR1 can modulate serotonin system. As I mentioned, TAAR1 is expressed within dorsal raphe nucleus. TAAR1 agonists decrease firing frequency of serotonin neurons in dorsal raphe. TAAR1 can balance serotonergic activity. There are several interesting reports are coming.
Glutamate system, TAAR1 is expressed in the prefrontal cortex and can regulate glutamate neurotransmission there. TAAR1 activation appears to prevent hyperglutamatergic state, thereby causing an increase in the activity of prefrontal cortex. It is not surprising that TAAR1 agonists open new perspective for schizophrenia, but not only to schizophrenia. TAAR1 agonists demonstrate potential antipsychotic like activity, demonstrate potential antidepressant like activity, potential pro-cognitive activity, and influence wakefulness, and in animals and in humans now, this paper up here.
Thus, based on TAAR1 localization as well as its ability to act as a rheostat for dopamine, serotonin, and glutamate, TAAR1 agonist have the potential to serve as a therapeutic targets for several mental disorders including schizophrenia, depression, and bipolar disorder. I would like to acknowledge this short list of people who was working with me on this topic for last 20 years, and these companies which provided me with funds, mice, reagents, without whom this work would be impossible. Thank you very much.
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