Trace Amines and Neurological Disorders: Potential Mechanisms and Risk Factors

manuscript.

Section I

Introduction and Description of Trace Amines and Trace Amine-Associated Receptors

Outline

Chapter 1 Trace Amines: An Overview

Chapter 2 Methods of Trace Amine Analysis in Mammalian Brain

Chapter 3 Synthesis and Neurochemistry of Trace Amines*

Chapter 4 The Origin and Evolution of the Trace Amine-Associated Receptor Family in Vertebrates

Chapter 5 Differential Modulation of Adrenergic Receptor Signaling by Octopamine, Tyramine, Phenylethylamine, and 3-Iodothyronamine

Chapter 6 Effects of Trace Amines on the Dopaminergic Mesencephalic System

Chapter 7 Trace Amine-Associated Receptors in the Cellular Immune System

Chapter 8 Trace Amines and Their Receptors in the Control of Cellular Homeostasis

Chapter 9 Trace Amine-Associated Receptor 1 Modulation of Dopamine System

Chapter 10 Trace Amines as Intrinsic Monoaminergic Modulators of Spinal Cord Functional Systems

Chapter 11 Trace Amine-Associated Receptors: Ligands and Putative Role in the Central Nervous System

Chapter 12 β-Phenylethylamine Requires the Dopamine Transporter to Release Dopamine in Caenorhabditis elegans

Chapter 1

Trace Amines

An Overview

T. Roeder,    Department of Zoology, Molecular Physiology, Kiel University, Kiel, Germany

Abstract

Trace amines (TAs) are usually defined as monoamines that fulfill a set of criteria; they do not act as classical neurotransmitters in vertebrates, they are present in only minute amounts in the brain and they have a sympathomimetic activity. Compounds such as phenylethanolamine, octopamine, tyramine, and synephrine are typical TAs. Recent deorphanization of bioamine receptors revealed that a number of different receptors in the mammalian brain react at nanomolar concentrations to these compounds.

Two TAs, the monoamines octopamine and tyramine, act as regular transmitters in invertebrates where they take the roles of epinephrine and norepinephrine that are absent in these organisms. The corresponding signaling systems comprising the amines and their receptors, attracted the interest of invertebrate neurobiologists as these systems combine surprising similarities with the architecture and functioning of vertebrate adrenergic systems with a highly specific receptor pharmacology, making them valid targets for specific insecticides.

Keywords

Octopamine; tyramine; TAAR; olfactory receptor; invertebrate

Outline

Introduction 3

Trace Amine-Associated Receptors 5

TAs in Invertebrates 6

Conclusion 7

References 8

Introduction

Biogenic amines such as epinephrine, norepinephrine, dopamine, serotonin, or histamine act as classical neurotransmitters or neuroactive compounds in the mammalian central nervous system. They are involved in the regulation of countless behaviors and take central roles for the proper functioning of the nervous system in general. Consequently, deregulation of aminergic signaling has been associated with a great number of neurological diseases such as Parkinson’s disease, schizophrenia, depression, and many others. Moreover, biogenic amine metabolism is central to our reward system, thus being centrally involved in almost all types of drug action and the development of addiction. Taking this importance into account, synthesis, storage, but also removal of these biogenic amines is tightly regulated in order to keep their concentrations in physiologically relevant ranges. Termination of aminergic signaling is usually achieved by the combined action of specific reuptake systems and their enzymatic degradation. A complex web of enzymatic activities is required to regulate synthesis of these bioactive amines, but it also produces intermediate products and so-called trace amines (TAs) (Fig. 1.1).¹–³

Figure 1.1 Biosynthesis pathways that give rise to TAs. Starting with the amino acids phenylalanine and tyrosine, two enzymes, the aromatic L-amino acid decarboxylase (AADC) and the biopterin-dependent aromatic amino acid hydroxylases (AAAH) produce phenethylamine, tyramine (AADC), and L-3,4-diidroxyphenylalanine (L-DOPA, AAAH), respectively. In invertebrates the tyrosine decarboxylase (TDC) produces tyramine from tyrosine. Moreover, the AADC also produces dopamine from L-DOPA. The phenylethanolamine N-methyltransferase (PNMT) catalyzes a number of different reactions including the production of N-methylphenethylamine from phenethylamine. Octopamine is, on the other hand, produced by the dopamine β-monooxygenase (DBH). In invertebrates, this is achieved by the tyramine β-hydroxylase (TβH). DBH is also responsible for the synthesis of norepinephrine from dopamine. Finally, the catechol-O-methyltransferase (COMT) converts dopamine into 3-methoxytyramine. TAs are marked by gray boxes and the enzymes that are required to produce tyramine and octopamine in invertebrates are shown in bold and italics.¹–³

In order to elicit physiological responses in target cells, sets of highly specific receptor molecules tailored to transmit only information carried by the specific biogenic amines are utilized. This set of receptors for biogenic amines has been used extensively as targets for countless therapeutic interventions using specific receptor agonists and/or antagonists. In addition to this handful of biogenic amines that are present at high levels in the mammalian central nervous system, other amines have been described that were found only in very low concentration. Consequently, these amines have been named TAs. As already pointed out, TAs are connected to the classical aminergic transmitter substances as they are usually produced within the same network of enzymes giving rise to these compounds. The very low concentration of TAs and the lack of information about specific receptor molecules led for several decades to the assumption that TAs have no particular transmitter or hormone function in the mammalian nervous system. This situation was changed only recently with the identification of a particular class of G-protein-coupled receptors named trace amine activated receptors (TAARs).⁴ The original definition of the term TAs was very vague; usually, they are defined as monoamines that fulfill a small set of criteria: (1) they do not act as classical neurotransmitters in vertebrates; (2) they are present in only minute amounts (mostly in the nanomolar range) in the mammalian brain; and (3) they usually have a sympathomimetic activity. Compounds such as phenylethanolamine, octopamine, tyramine, tryptamine, and synephrine are typical TAs (Fig. 1.1). Despite the fact that their particular physiological role was mostly neglected, deregulation of their concentration have been linked to numerous psychotic disorders such as depression, schizophrenia, migraine, or attention deficit hyperactivity disorder. The synthesis pathways that give rise to the different biogenic amines, as well as to the TAs listed above, are shown in Fig. 1.1.¹,² Interestingly, both, conventional biogenic amines with an unequivocal transmitter function as well as the TAs share the same synthesis network comprising of proteins with the corresponding enzymatic activities. One early explanation for the presence of TAs was that they are unavoidable byproducts of these complex synthesis pathways.

More than 10 years ago, deorphanization of bioamine receptors revealed that a number of different receptors in the mammalian brain react at nanomolar concentrations to TAs. These receptors called trace amine-associated receptors (TAARs) revitalized the interest in studying the biology of TAs dramatically.⁴ A more detailed characterization of TAARs is found below.

The second highly interesting area of research where TAs have been focused on is their physiological role in invertebrates. Two of these TAs, octopamine, and tyramine, act as highly potent and highly important transmitter compounds in almost all invertebrates. In these animals they take the role of the classical aminergic neuroactive compounds epinephrine and norepinephrine. As for the TAARs, the role of TAs in invertebrates will be introduced below.

Trace Amine-Associated Receptors

In 2001, deorphanization of G-protein-coupled receptors revealed that TAs specifically activate some receptor molecules.⁵,⁶ The first member of this family name trace amine-associated receptor 1 (TAAR1), was shown to be specifically activated by a set of TAs including phenylethanolamine (PEA) and tryptamine in the micro- to nanomolar range. TAAR1 was the founding member of a new family of GPCRs that shares significant similarities with members of the conventional biogenic amine receptor families. Apparently, the occurrence of TAARs is tightly associated with vertebrate evolution; thus this family of GPCRs is absent in invertebrates.⁷,⁸ In humans only six TAARs were found, while rodents have more than twice the number of TAAR genes in their genomes (17 in rats and 15 in mice). In fish genomes, a highly variable number of genes can be assigned to the TAAR family. While some fish species, such as some cichlids (from 12 to 44) or the pufferfish Fugu (13) have gene number very similar to those seen in rodents, others, such as the zebrafish contain more than 100 different TAAR genes.⁹ Despite the structural similarities shared by all known members of the TAAR family, more detailed analyses revealed that this group could be further divided into two or three subclasses based on their primary structures. Despite naming the entire family of proteins TAARs, most of them are insensitive towards confrontation with classical TAs. Only TAAR1 has unequivocally been shown to be sensitive to TA confrontation, responding with specific activation and a suitable physiological response.¹⁰ Research in recent years was dichotomous with regard to the TAAR family. While a modulatory role in the nervous system that controls the activities of biogenic amine receptors and transporters has been assigned to some of them (eg, TAAR1), others are obviously olfactory receptors specifically tuned to detect volatile amines.¹¹

Nanomolar concentrations of some TAs could specifically activate TAAR1. Tyramine and PEA are the most effective, meaning that they have the potential to induce the full agonistic response at the lowest concentrations. Binding of the agonists activates the Gαs G-protein, thus leading to an increase in cyclic AMP (cAMP) levels. The major function of TAAR1 appears to be restricted to monoaminergic systems. Different aspects in these monoaminergic systems, more precisely in dopaminergic and serotonergic systems, are regulated by neurotransmission involving TAARs. Especially dopaminergic and serotonergic systems are involved, presumably via regulation of the corresponding uptake systems. These neuronal systems are tightly associated with a set of different neuronal disorders. Newly synthesized TAAR1 agonists gained substantial interest as they might have potent anxiolytic and antipsychotic effects.¹²,¹³

As already pointed out, the second group of TAARs that are not involved in regular aminergic signaling have been identified as olfactory receptors. They are tailored to recognize volatile amines, thus complementing the comprehensive set of conventional olfactory receptors in order to generate the complete olfactory input.¹⁴ These receptors are expressed within the olfactory system utilizing its signal transduction machinery.¹⁵ The different TAARs that are part of the olfactory system recognize different amines, thus covering a complex set of volatile compounds that are relevant for the organism’s survival.¹⁶,¹⁷ The volatile amines are often components of urine or feces, thus, they give information about conspecifics or potential predators. Functionally these volatile amines with high information content often serve as phero- or kairomones.¹⁸,¹⁹ Consequently, some of these volatile amines induce attraction, while others lead to aversive reactions. It is still a matter of debate, whether the primary ligands for the founding members of this family were indeed TAs or volatile amines. Thus, it is still not clear whether the olfactory system hijacked this part of the aminergic system or if aminergic signaling used this primarily olfactory system.

TAs in Invertebrates

Only two TAs, the monoamines octopamine and tyramine, yielded substantial interest of neurobiologists and pharmacologists focusing on invertebrates as they take very particular roles in invertebrates. In contrast to the situation found in the mammalian brain, both amines are present at very high concentrations throughout the nervous systems of almost all invertebrates studied so far. They act as regular transmitters in these animals, where they take the roles of epinephrine and norepinephrine that are mostly absent or present in only minor amounts in invertebrates, thus representing invertebrate TAs. Since its discovery more than 60 years ago,²⁰ octopamine became a pet compound of invertebrate neurobiologists and pharmacologists. The source from which octopamine was first isolated gave it its name, the salivary glands of Octopus, where it could be found in millimolar concentrations.²⁰ Tyramine, on the other hand, functions as the biological precursor of octopamine, but has its own physiological role, independent of octopamine.³,²¹,²² Nevertheless, the problems associated with disentangling the roles of octopamine and tyramine led most researchers to focus on octopamine rather than on tyramine.²³ Despite the fact that both monoamines are TAs in the vertebrate nervous system, their naming as TAs in the context of invertebrate neurobiology is not really justified.

Mostly, vertebrates and invertebrates use the same biogenic amines in similar functional contexts. Only the adrenergic signaling compounds make an exception to this generally applicable rule. While epinephrine and norepinephrine are the adrenergic compounds operative in vertebrates, their role is taken by octopamine and tyramine in invertebrates. Structurally, these compounds are highly related, with the major difference being that epinephrine and norepinephrine are catecholamines, while octopamine and tyramine carry only a single hydroxyl group at their phenolic ring. Despite the fact that the structures of the signaling compounds differ, adrenergic systems of vertebrates and invertebrates share a surprisingly high degree of functional and architectural similarities. Compounds are released in very similar conditions and they control or modulate very similar physiological aspects of life, which implies that the last common ancestor of vertebrates and invertebrates already had a well-defined adrenergic system that was in charge of controlling very similar aspects of life.²⁴ Apparently, either the progenitors of vertebrates or those of invertebrates switched from using epinephrine/norepinephrine to octopamine/tyramine or vice versa.

Beside the multifarious role of octopamine and tyramine for the control of different behaviors, they are also responsible for modulation of a great variety of different peripheral organs in order to adapt their physiology to the needs of the organism in a particular situation. Octopamine is centrally involved in the control of learning and memory, but also part of the neurochemical circuitry that controls aggression.²⁵,²⁶ Moreover, this neuroactive compound is able to modulate the input of different sensory organs at different levels and it appears to take a decisive role for controlling various aspects of movement activity.²⁷–²⁹ Receptors that transmit the physiological effects of octopamine and tyramine are all G-protein-coupled, but they share no homologies with the TAAR receptor families.³⁰ In contrast, they are classical biogenic amine receptors, clustering together with vertebrate α- or β-adrenergic receptors.³¹,³² As octopamine and tyramine receptors are the only invertebrate amine receptors that have no direct counterparts in vertebrates, they attracted the interest of invertebrate neurobiologists. Octopamine receptors were specially chosen as targets for highly specific agonists.³³ Compounds with affinities in the subnanomolar range have been developed and some of them, including amitraz and chlordimeform, have been extensively used as insecticides.³⁴,³⁵

Conclusion

Research within the field of TAs has developed from an exotic subject into different flourishing research areas. In the invertebrate field, octopamine and tyramine, as typical TAs, developed into the most interesting amines, attracting a larger number of researchers to this field, as these monoamines function as regular transmitters, involved in regulating a plethora of behaviors and physiological processes. The situation in the vertebrate field completely changed after identification of the first TAAR in 2001. Identification of this new family of G-protein receptors has led to the emergence of two completely new fields of research: (1) the role of TAs in regulation of monoaminergic systems and (2) the activity of TAARs as highly specific odorant receptors tailored to detect volatile amines, thus representing receptors for various phero- and kairomones. These developments will be presented in depth in the different chapters of this book.

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