Trace Amines and Their Receptors

72 Pages·2017·2.05 MB·English

1521-0081/70/3/549–620$35.00 https://doi.org/10.1124/pr.117.015305
PHARMACOLOGICALREVIEWS PharmacolRev70:549–620,July2018
Copyright©2018byTheAuthor(s)
ThisisanopenaccessarticledistributedundertheCCBY-NCAttribution4.0Internationallicense.
ASSOCIATEEDITOR:JEFFREYM.WITKIN
Trace Amines and Their Receptors
RaulR.Gainetdinov,MariusC.Hoener,andMarkD.Berry
InstituteofTranslationalBiomedicine,St.PetersburgStateUniversity,St.Petersburg,Russia(R.R.G.);SkolkovoInstituteofScienceand
Technology(Skoltech),Moscow,Russia(R.R.G.);Neuroscience,Ophthalmology,andRareDiseasesDiscoveryandTranslationalArea,
pRED,RocheInnovationCentreBasel,F.Hoffmann-LaRocheLtd.,Basel,Switzerland(M.C.H.);andDepartmentofBiochemistry,
MemorialUniversityofNewfoundland,St.John’s,NewfoundlandandLabrador,Canada(M.D.B.)
Abstract.....................................................................................551
I. Introduction.................................................................................551
II. Vertebrate Trace Amines....................................................................555
A. b-Phenylethylamine, p-Tyramine, and Related Compounds ...............................555
1. Synthesis ............................................................................555
a. Regulation of Aromatic L-Amino Acid Decarboxylase...............................555
b. Other Sources of b-Phenylethylamine, p-Tyramine, and Related Compounds .......560
i. Microbiota-Derived Trace Amines...............................................560
ii. Food-Derived Trace Amines ....................................................561
2. Degradation..........................................................................561
3. Storage and Passage across Membranes ..............................................561
4. Cellular Effects ......................................................................562
a. Indirect Sympathomimetic Responses .............................................562
b. b-Phenylethylamine...............................................................562
c. p-Tyramine.......................................................................564
d. Tryptamine.......................................................................564
D
e. Octopamine.......................................................................565 o
5. b-Phenylethylamine, p-Tyramine, and Tryptamine in Human Disorders...............565 w
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B. Isoamylamine ...........................................................................566 lo
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C. Trimethylamine .........................................................................566 d
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D. O-Methyl and N-Methyl Derivatives .....................................................568 f
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E. 3-Iodothyronamine.......................................................................568 o
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1. Cardiovascular Effects................................................................569 p
2. Metabolic Effects.....................................................................569 h
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3. Thermoregulation ....................................................................569 rm
4. Other Effects.........................................................................570 re
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F. Polyamines..............................................................................570 .a
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G. Putative Other Trace Amines............................................................571 p
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III. Invertebrate Trace Amines ..................................................................571 tj
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A. Synthesis and Degradation ..............................................................571 u
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B. Storage and Release.....................................................................571 a
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C. Octopamine Receptors ...................................................................572 .o
D. Tyramine Receptors .....................................................................572 rg
E. Physiologic Responses ...................................................................572 at
A
1. Octopamine ..........................................................................572
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2. Tyramine ............................................................................573 P
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IV. Trace Amine–Associated Receptors ..........................................................573 T
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Address correspondence to: Raul R. Gainetdinov, Institute of Translational Biomedicine, St. Petersburg State University, s
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UniversitetskayaEmb.7-9,199034St.Petersburg,Russia.E-mail:[email protected] n
This work was supported by the Russian Science Foundation [Grant 14-50-00069 (to R.R.G.)] and the Research and Development M
CorporationofNewfoundlandandLabradorandMemorialUniversityofNewfoundland(toM.D.B.). a
r
R.R.G.,M.C.H.,andM.D.B.contributedequallytothiswork. c
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https://doi.org/10.1124/pr.117.015305. 1
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550 Gainetdinovetal.
A. Evolution of Trace Amine–Associated Receptors..........................................577
B. Trace Amine–Associated Receptor 1......................................................578
1. Pharmacology of Trace Amine–Associated Receptor 1 .................................584
a. Trace Amine–Associated Receptor 1 Gene Conservation............................584
b. Expression of Trace Amine–Associated Receptor 1 .................................584
c. Trace Amine–Associated Receptor 1 Ligands.......................................588
i. Development of Selective Agonists and Partial Agonists.........................589
ii. Development of N-(3-Ethoxyphenyl)-4-(1-Pyrrolidinyl)-3-(Trifluoromethyl)
Benzamide, the First Selective Antagonist.........................................589
d. Signal Transduction and Molecular Interactions ...................................590
i. Adenylyl Cyclase...............................................................590
ii. G Protein–Coupled Inwardly Rectifying Potassium Channels....................590
iii. Heterodimerization with the D2-Like Dopamine Receptor.......................590
iv. b-Arrestin 2 and Biased Signaling..............................................592
v. Other Signaling Cascades......................................................592
2. Central Nervous System Effects ......................................................592
a. Cellular Effects ...................................................................592
i. Dopaminergic Systems .........................................................592
ii. Serotonergic Systems...........................................................594
iii. Glutamatergic Systems ........................................................594
b. Behavior..........................................................................595
i. Schizophrenia and Bipolar Disorder ............................................595
ii. Cognitive Effects ...............................................................595
iii. Depression ....................................................................595
iv. Sleep, Wake, and Narcolepsy...................................................596
v. Addiction and Compulsive Behaviors...........................................596
vi. Feeding Behavior..............................................................597
3. Effects in the Periphery..............................................................598
a. Diabetes and Obesity.............................................................598 D
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b. Immunomodulatory Effects .......................................................598 w
c. Cancer ...........................................................................599 n
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d. Pregnancy........................................................................599 a
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C. Other Tetrapod Trace Amine–Associated Receptors.......................................599 e
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1. Trace Amine–Associated Receptor 2..................................................599 f
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2. Trace Amine–Associated Receptor 3..................................................600 m
3. Trace Amine–Associated Receptor 4..................................................600 p
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4. Trace Amine–Associated Receptor 5..................................................600 a
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5. Trace Amine–Associated Receptor 6..................................................601 m
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6. Trace Amine–Associated Receptor 7..................................................601 ev
7. Trace Amine–Associated Receptor 8..................................................601 .as
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8. Trace Amine–Associated Receptor 9..................................................602 e
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ABBREVIATIONS: 3-MT, 3-methoxytyramine; 3IT, 3-iodothyronamine; 5-HT, 5-hydroxytryptamine; AADC, aromatic L-amino acid rn
decarboxylase; AKT, protein kinase B; AMPA, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; AOC3, amine oxidase, copper al
s
containing 3; ASIC, acid-sensing ion channel; COMT, catechol-O-methyltransferase; CPP, conditioned place preference; D1R, D1-like .o
dopamine receptor; D2R, D2-like dopamine receptor; DAT, dopamine transporter; DMT, N,N-dimethyltryptamine; DRL, differential rg
reinforcementoflowresponserate;DRN,dorsalraphenuclei;EAAT-2,excitatoryaminoacidtransporter2;EPPTB,N-(3-ethoxyphenyl)-4-(1- a
t
pyrrolidinyl)-3-(trifluoromethyl)benzamide (also known as RO5212773); FMO3, flavin monooxygenase 3; GLP-1, glucagon-like peptide 1; A
GPCR, G protein–coupled receptor; GSK3b, glycogen synthase kinase; HEK-293, human embryonic kidney 293; IUPHAR, International S
P
UnionofBasicandClinicalPharmacology;KO,knockout;L-687,414,(3S,4S)-3-amino-1-hydroxy-4-methylpyrrolidin-2-one;MAO,monoamine E
oxidase; MDMA, 3,4-methylenedioxymethamphetamine; MHC, major histocompatibility complex; NMDA, N-methyl-D-aspartate; NREM, T J
nonrapid eye movement; OAMB, octopamine receptor in mushroom bodies; OCT, octopamine; OCT2, organic cation transporter 2; OE, o
overexpressing;PCP,phencyclidine;PEA,b-phenylethylamine,2-phenylethylamine;phMRI,pharmacologicalmagneticresonanceimaging; ur
n
PKA, protein kinase A; PKC, protein kinase C; PNMT, phenylethanolamine-N-methyl transferase; PYY, peptide YY; RO5166017, (S)- a
l
4-((ethyl(phenyl)amino)methyl)-4,5-dihydrooxazol-2-amine; RO5203648, (S)-4-(3,4-dichlorophenyl)-4,5-dihydrooxazol-2-amine; RO5256390, s
o
(S)-4-((S)-2-phenylbutyl)-4,5-dihydrooxazol-2-ylamine; RO5263397, (S)-4-(3-fluoro-2-methylphenyl)-4,5-dihydrooxazol-2-amine; S18616, (S)- n
spiro[(1-oxa-2-amino-3azacyclopent-2-ene)-4,29-(89-chloro-19,29,39,49-tetrahydronaphthalene)]; SKF-82958, 6-chloro-7,8-dihydroxy-3-allyl-1- M
phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine;SSAO,semicarbazide-sensitiveamineoxidase;TA,traceaminereceptor;TAAR,traceamine– a
r
associatedreceptor;TMAO,trimethylamine-N-oxide;TRP,tryptamine;TYR,p-tyramine;UGT,uridinediphosphateglucuronosyltransferase; c
h
VAP-1,vascularadhesionprotein-1;VTA,ventraltegmentalarea. 1
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TraceAminesandTheirReceptors 551
D. Trace Amine–Associated Receptors in Teleost and Other Fish................................602
E. Trace Amine–Associated Receptors in Olfaction..............................................603
1. Trace Amine–Associated Receptor 2......................................................604
2. Trace Amine–Associated Receptor 3......................................................604
3. Trace Amine–Associated Receptor 4......................................................604
4. Trace Amine–Associated Receptor 5......................................................604
5. Trace Amine–Associated Receptors 7, 8, and 9 ...........................................605
6. Teleost Olfactory Responses..............................................................605
V. Future Directions ...........................................................................606
A. Better Understanding of the Physiologic Role(s) of Trace Amine–Associated Receptors
and Their Endogenous Ligands ..........................................................606
1. Trace Amine–Associated Receptor 1 ..................................................606
2. Other Trace Amine–Associated Receptors.............................................606
B. DevelopmentofSelectiveTraceAmine–AssociatedReceptor1LigandsasTherapeutics ...606
1. Schizophrenia and Bipolar Disorder ..................................................606
2. Addiction and Compulsive Behaviors .................................................607
3. Metabolic Syndromes.................................................................608
C. Trace Amine–Associated Receptors in Ecology............................................608
D. Trace Amine–Associated Receptors, Nutrition, the Microbiome, and Health...............609
VI. Conclusion ..................................................................................609
Acknowledgments...........................................................................610
References ..................................................................................610
Abstract——Trace amines are endogenous com- olfactoryepitheliumneurons,wheretheydetectdiverse
pounds classically regarded as comprising b-phenyl- ethological signals including predators, spoiled food,
ethyalmine, p-tyramine, tryptamine, p-octopamine, migratory cues, and pheromones. Outside the olfactory
andsomeoftheirmetabolites.Theyarealsoabundant system,TAAR1isthemostthoroughlystudiedandhas
in common foodstuffs and can be produced and de- bothcentralandperipheralroles.Inthebrain,TAAR1
graded by the constitutive microbiota. The ability to actsasarheostatofdopaminergic,glutamatergic,and D
o
use trace amines has arisen at least twice during serotonergicneurotransmissionandhasbeenidentified w
evolution, with distinct receptor families present in asanoveltherapeutictargetforschizophrenia,depression, n
l
invertebrates and vertebrates. The term “trace amine” and addiction. In the periphery, TAAR1 regulates o
a
was coined to reflect the low tissue levels in mammals; nutrient-induced hormone secretion, suggestingits d
e
however,invertebrateshaverelativelyhighlevelswhere potential as a novel therapeutic target for diabetes d
f
they function like mammalian adrenergic systems, in- and obesity. TAAR1 may also regulate immune r
o
volvedin“fight-or-flight”responses.Vertebratesexpress responses by regulating leukocyte differentiation and m
a family of receptors termed trace amine–associated activation. This article provides a comprehensive p
h
receptors (TAARs). Humans possess six functional reviewofthecurrentstateofknowledgeoftheevolution, a
r
isoforms (TAAR1, TAAR2, TAAR5, TAAR6, TAAR8, and physiologic functions, pharmacology, molecular m
TAAR9), whereas some fish species express over 100. mechanisms, and therapeutic potential of trace amines re
With the exception of TAAR1, TAARs are expressed in andtheirreceptorsinvertebratesandinvertebrates. v
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I. Introduction below those of the corresponding neurotransmitters jo
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(Berry, 2004). With the close structural similarity to r
Although vertebrate receptors showing a high selec- n
the monoamine neurotransmitters a central driving al
tivity for trace amines have been known for approxi- s
forcebehindmuchoftheprereceptorresearch,theterm .o
mately 15 years (Borowsky et al., 2001; Bunzow et al., r
2001), research and interest in the endogenous com- traceaminesubsequentlybecamesynonymouswithjust ag
asmallgroupofendogenousmonoamines—inparticular, t A
pounds now known as trace amines dates back almost
b-phenylethylamine (PEA), p-tyramine (TYR), trypt- S
150years.Theterm“traceamine”itselfappearstohave P
amine (TRP), and p-octopamine (OCT), the compounds E
beencoinedinthe early1970sbyAlanBoultonandhis T
that have the most obvious similarity to the well J
colleagues (Boulton, 1974) as a way to distinguish a o
establishedmonoamineneurotransmitters(Fig.1). u
groupofendogenousvertebratemonoaminesfromtheir The earliest known reports of the presence of a rn
a
more abundant close structural relatives, the catechol- compoundwithachemicalcompositionconsistentwith ls
o
amine and indoleamine neurotransmitters (Fig. 1). The one of the trace amines (PEA) is from work in the n
original intent of the term “trace” was to emphasize laboratoryofMarceliNenckiduringthelate1870s(see M
a
the low endogenous tissue concentrations present Grandy, 2007), aimed at better understanding the rc
(,10 ng/g; 100 nM), at levels that are at least 100-fold bacterial processes of putrefaction and fermentation. h 1
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Duringthesestudies,PEAwasshowntobeaproductof abuse.Furthermore,amphetamine(anditsderivatives)
bacterial decomposition of both gelatin and egg white, has a strong structural similarity to the trace amines,
due to the anaerobic decarboxylation of L-phenylala- particularly PEA (Fig. 2). As such, PEA and TYR, to a
nine. PEA was subsequently found to be produced as lesser extent, became of interest as potential “endoge-
part of the decomposition processes of various other nous amphetamines” (Borison et al., 1975; Janssen
animal-derivedproteins,alongwiththefirstreportsof etal.,1999).Thisalsopoweredaninterestinthetrace
its presence in fermented foodstuffs. This ready pro- amines aspossiblebiomarkersandetiologicfactorsfor
duction of trace amines by microbiota has often been psychiatric disorders, and extensive tabulations of
overlooked in more recent years; as described in sub- changes in the levels of endogenous trace amines and
sequentsections,however,recentincreased interestin their metabolites in various body fluids were compiled
the role of host-microbiome interactions and dietary (Davis, 1989). Although most groups were content to
components in health and disease suggests that such rely on the amphetamine-like, indirect sympathomi-
productionislikelytogatherrenewedinterest. meticeffectsoftraceaminesasamechanisticexplana-
The initial demonstrations of biologic effects of PEA tionforobservedeffects,asmallnumberofresearchers
andTYRareintricatelylinkedtotheveryoriginsofthe beganacarefulexaminationoftheneuropharmacology
field of pharmacology. The isolation of both PEA and of more physiologically relevant concentrations. Most
TYR from biologic sources such as rotting horsemeat notable among this latter group were those affiliated
and ergot-contaminated grains (the original use of the withtheNeuropsychiatryResearchUnitinSaskatoon,
term ergotamine was to describe TYR) led to the Canada,underthedirectorshipofAlanA.Boulton,and
pioneeringstudiesofGeorgeBarger,GeorgeS.Walpole, anumberoftheirstudiesaredescribedinlatersections.
SirHenryHallettDale,andAlfredJ.Clark(Bargerand Althoughanumberofeffectswereobserved,thissecond
Walpole, 1909; Barger and Dale, 1910; Clark, 1911), phaseofstudiesinvertebratesstalledduetothelackof
demonstrating pronounced blood pressure–elevating a selective receptor target through which the observed
effects of the purified extracts. Although interest in effects could be mediated. In contrast, TYR and OCT
the compounds continued and their presence was wereestablishedasbonafideinvertebrateneurotrans-
confirmedineveryspeciesinwhichtheywereexamined mitters during the same time period, with selective
(see Berry, 2004), research into the trace amines receptors identified (Morton and Evans, 1984; Roeder
graduallyfadedawayasinterestinthemoreabundant and Gewecke, 1989; Han et al., 1998; Consoulas et al.,
monoaminespeciesnorepinephrine,epinephrine,dopa- 1999). Thus, by the early 1990s, trace amine research D
o
mine and serotonin surged. As the new discipline of wasessentiallyrestrictedtoinvertebratesystems. w
pharmacology developed and the chemical basis of The picture changed again in 2001 when a family of n
l
o
neurotransmission became accepted, the following cri- vertebrate G protein–coupled receptors (GPCRs) was a
d
teria for endogenous compounds to be considered identified,asubsetofwhichshowedhighselectivityfor e
d
neurotransmitters were developed: 1) the presence of PEA, TYR, and OCT (Borowsky et al., 2001; Bunzow f
r
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the compound and its biosynthetic enzymes limited to et al., 2001).Interestingly, the receptorswere foundto m
thesitesatwhichapplicationoftheexogenouschemical be evolutionarily distinct from the invertebrate TYR p
h
(at physiologic concentrations) elicits responses; 2) andOCTreceptors(Lindemannetal.,2005),indicating a
r
m
release of the compound occurs on nerve stimulation thattheabilitytodetecttraceamineshasarisenatleast
r
e
with no (or minimal) release in the absence of nerve twiceduringevolution.Thisresurrectedinterestinthe v
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stimulation; 3) exogenous application of physiologic vertebrate trace amine system. As detailed elsewhere s
p
concentrationsmimicstheeffectsofnervestimulation; (Berryetal.,2017),however,thenewfamilyofreceptors e
t
j
and 4) responses to nerve stimulation and exogenous has posed a number of unique challenges that have o
u
chemical application are affected in the same manner slowedprogressanddissuadedmanyfromestablishing rn
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by pharmacological agents. Unfortunately, at least in (andfunding)dedicatedtraceamineresearchprograms. ls
vertebratesystems,none ofthetraceaminesmetmost, A brief history of the discovery of this family of .o
r
g
if any, of these criteria, and the compounds became receptors, and their subsequent naming as trace a
increasingly viewed as little more than metabolic amine–associated receptors (TAARs), is provided in t A
by-products. IV.TraceAmine–AssociatedReceptors.Notwithstanding S
P
With the growing use of psychotropic drugs in the the difficulties, the last 15 years have seen a number of E
T
1960s, and amphetamine-based compounds in particu- advances that have identified trace amines and their J
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lar, a resurgence of interest in the trace amines was receptors as novel targets for the pharmacotherapy of u
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seen. Although researchers had struggled to demon- variousdisorders,aswellasbeingnovelsitesforenviron- na
l
strate responses to PEA or TYR at endogenous tissue mentalchemicalinteractionsleadingtobehavioralecology s
o
concentrations, both were well established to have effects.Althoughanumberofexcellentreviewsfocusingon n
M
indirect sympathomimetic properties at supraphysio- individualsubareasoftraceaminepharmacology,partic-
a
logicconcentrations(Fuxeetal.,1967),effectsthatwere ularlyinrelationtoTAAR1,havebeenpublished(Grandy, rc
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shared with the new amphetamine-based drugs of 2007;Sotnikovaetal.,2008;JingandLi,2015;Lametal., 1
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TraceAminesandTheirReceptors 553
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Fig.1. Relationshipofarchetypaltraceaminestothemonoamineneurotransmitters. rn
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2015;Liberles,2015;Peietal.,2016;Berryetal.,2017),a a comprehensive overview of the current state of the
a
comprehensive review of all aspects of trace amine knowledge of trace amine systems throughout the body, rc
h
pharmacologyislacking.Thisarticleaimstoprovidesuch inbothvertebratesandinvertebrates. 1
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554 Gainetdinovetal.
Beforewebegin,however,itisworthwhiletodiscuss and spermidine (Saraiva et al., 2016). In addition, the
the definition of the term “trace amine.” As described N-methylated metabolites of both PEA and TYR, N-
above, this term is generally accepted to comprise the methylphenylethylamine and N-methyltyramine, are
group of compounds formed when the tyrosine hydrox- alsoTAARagonists(LindemannandHoener,2005),as
ylase or tryptophan hydroxylase step of catecholamine is the N-methyl metabolite of TRP N,N-dimethyltryp-
and indoleamine neurotransmitter synthesis is omit- tamine (DMT); although in this latter instance, this
ted.ThepharmacologicalprobingoftheTAARfamilyin shows a strong species dependence (Simmler et al.,
various species, however, indicates that this is far too 2016). With a receptor family bearing the name trace
narrow a definition. A variety of other endogenous amine now present, we propose that a formalized
amines that function as selective agonists at one or workingdefinitionofthetraceaminetermbeadopted.
moreTAARfamilymembersarepresentinbodyfluids The rather broad substrate tuning that the TAAR
at low levels (Fig. 3) and these compounds are often family exhibits (described in detail in subsequent
associatedwithmetabolicroutesthataredistinctfrom sections)complicatesthedevelopmentofacleardefini-
those of the compounds traditionally called trace tion. For example, both dopamine and serotonin show
amines. Such compounds include the endogenous thy- partial agonistic activity at TAAR1 at physiologically
roid hormone metabolite 3-iodothyronamine (3IT) relevant concentrations (Lindemann et al., 2005) but
(Scanlanetal.,2004;Dinteretal.,2015c),thecatechol- would not be regarded as trace amines per se. The
amineneurotransmittermetabolites3-methoxytyramine situation is further complicated by TAARs only being
(3-MT) and normetanephrine (Bunzow et al., 2001; present in vertebrate systems, whereas invertebrates
Sotnikova et al., 2010), trimethylamine (Ferrero et al., have receptors that are selectively activated by TYR
2012; Wallrabenstein et al., 2013; Li et al., 2015), and OCT but are distinct from TAARs and are much
isoamylamine (Liberles and Buck,2006; Ferrero etal., morecloselyrelatedtovertebrateadrenergicreceptors
2012), the polyamines putrescine and cadaverine (Roeder, 2005; Lange, 2009). Indeed, as will be dis-
(Hussainetal.,2013),andpossiblyagmatine,spermine, cussed below, TYR and OCT are thought to fulfill the
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Fig.2. StructuresofsyntheticTAAR1ligands. 1
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TraceAminesandTheirReceptors 555
roleofadrenergicneurotransmissionininvertebrates,a The similarity to monoamine neurotransmitter syn-
situation that is distinctly different from their roles in thesishasoftenledtothesynthesisoftraceaminesbeing
vertebrate species. Correspondingly, invertebrate en- reported as neuronal. However, it should be borne in
dogenous levels of TYR and OCT are thought to be far mindthatAADCexpressionisnotrestrictedtoneuronal
greaterthanisthecaseforvertebrates(Roeder,2016). cells. AADC is present in a number of other cell types,
Furthermore, as will be discussed in subsequent sec- includingglia(Lietal.,1992b;Juorioetal.,1993),blood
tions, some “endogenous” ligands for TAARs may be vessels(Lietal.,2014),andcellsofthegastrointestinal
reliant on the constitutive microbiota for their pro- tract (Lauweryns and Van Ranst, 1988; Vieira-Coelho
duction.Wethereforeproposethataworkingdefinition and Soares-da-Silva, 1993), kidney (Christenson et al.,
ofthetermtraceamineshouldrecognizetheevolution- 1970;Lancaster andSourkes,1972;Aperia etal.,1990;
aryseparationofidenticalsignalingmoleculesbetween Hayashietal.,1990),liver(BouchardandRoberge,1979;
vertebrates and invertebrates, and it should take Ando-Yamamotoetal.,1987;Dominicietal.,1987),lungs
account of both the generally low vertebrate tissue (LauwerynsandVanRanst,1988;Linnoilaetal.,1993),
levels as well as a selective interaction with one or pancreas(LindströmandSehlin,1983;Furuzawaetal.,
more TAARs. This is an area in which engagement 1994;Rorsmanetal.,1995),andstomach(Lichtenberger
between the International Union of Basic and Clinical etal.,1982).Insuchcells,itcanreasonablybeexpected
Pharmacology(IUPHAR)nomenclaturecommitteeand that AADC will convert any precursor amino acids
thoseactiveinthetraceaminefieldwouldbeadvanta- present into the corresponding trace amine(s). The
geous.Forthepurposesofthisarticle,andasastarting physiologic function of AADC in non-neuronal tissue is
point for future discussions, we suggest that trace generally poorly understood but it does provide a
aminesbedefinedasfollows:atraceamineisanamine mechanismforthelocalproductionofligandsforTAARs
thatisendogenouslypresentinvertebratetissuesand/ thatarelocalizedtonon-neuronaltissue,andinvestiga-
orbodilyfluidsatconcentrations,50ng/gtissue(≲500 tionofpossiblecolocalizationofAADCwithTAARsisan
nM)andselectivelybindstooneormoreTAARsatthese areaforfuturestudies.Furthermore,adistinctgroupof
concentrations. neurons that contain AADC, but not tyrosine hydroxy-
laseorserotonin,arepresentinthemammaliancentral
nervoussystem(Jaegeretal.,1983,1984;Fetissovetal.,
II. Vertebrate Trace Amines
2009; Kitahama et al., 2009). These D-neurons offer a
A. b-Phenylethylamine, p-Tyramine, and
potentialtraceaminergicneuronalsystem. D
Related Compounds o
Although AADC is widely accepted as the vertebrate w
1. Synthesis. The archetypal trace amines are syn- syntheticenzymeforPEA,TYR,andTRP,theprecursor n
l
o
thesized after initial decarboxylation of precursor aminoacidsareinfactratherpoorsubstratesforAADC. a
d
aminoacids(Fig.4).Thispathwayisdirectlyanalogous Indeed,theKmvaluesfordecarboxylationofL-phenylal- ed
to the synthesis of the monoamine neurotransmitters, anine,L-tyrosine,andL-tryptophanapproachthelimits fr
o
with the trace amines being the end product if the of solubility of each in aqueous media (Christenson m
tyrosine hydroxylase (EC 1.14.16.2) or tryptophan et al., 1970; Juorio and Yu, 1985a). Although this is p
h
hydroxylase (EC 1.14.16.4) steps of neurotransmitter markedly, and selectively, improved both in vitro and a
r
m
synthesisareomitted.Assuch,PEA,TYR,andTRPcan in vivo by the presence of organic solvents (Lovenberg
r
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be formed directly by the action of aromatic L-amino et al., 1962; Juorio and Yu, 1985a,b), this does raise v
.a
aciddecarboxylase(AADC; EC4.1.1.28)onL-phenylal- questions about how PEA, TYR, and TRP are being s
p
anine, L-tyrosine, and L-tryptophan, respectively synthesized in vivo. Substrate-selective regulation of et
j
(Boulton and Wu, 1972, 1973; Saavedra, 1974; AADC has been reported (Bender and Coulson, 1972; o
u
Snodgrass and Iversen, 1974; Silkaitis and Mosnaim, SimsandBloom,1973;Simsetal.,1973;Rahmanetal., rn
a
1976; Dyck et al., 1983). Both m- and o-isoforms of 1981; Siow and Dakshinamurti, 1985), along with a ls
tyraminehavealsobeenidentifiedbuthaverarelybeen number of splice variants of the enzyme (O’Malley et .o
r
g
studied,andtheyarepresentinevensmallerquantities al., 1995; Rorsman et al., 1995; Chang et al., 1996; a
t
than the p-isoforms (Boulton, 1976; Davis, 1989). OCT Vassilacopoulou et al., 2004). Whether one or more of A
and p-synephrine can subsequently be formed by the theseexhibitsenhancedselectivityfortheproductionof S
P
sequential action of dopamine-b-hydroxylase (EC PEA, TYR, and/or TRP requires systematic investiga- E
T
1.14.17.1) (Boulton and Wu, 1972, 1973) and phenyl- tion. Furthermore, L-phenylalanine, L-tyrosine, and L- J
o
ethanolamine-N-methyl transferase (PNMT; EC tryptophanareallalsosubstratesforadditionalamino u
r
2.1.1.28). The trace amines can also undergo N-meth- aciddecarboxylaseenzymes(Table1),althoughtherole na
l
ylation by action of the enzymes PNMT or indolethyl- of these putative additional sources of PEA, TYR, and s
o
amine N-methyltransferase (EC 2.1.1.49) to generate TRPsynthesishasnotyetbeeninvestigated. n
M
additional TAAR ligands, N-methylphenylethylamine, a.RegulationofAromaticL-AminoAcidDecarboxylase.
a
N-methyltyramine, N-methyltryptamine, and, at least Asdescribedabove,AADCisfoundinbothneuronaland rc
h
insomespecies,DMT(Fig.4). non-neuronal cells and alternative splicing of exons 1
3
, 2
0
2
3
556 Gainetdinovetal.
D
o
w
n
l
o
a
d
e
d
f
r
o
m
p
h
a
r
m
r
e
v
.a
s
p
e
t
j
o
u
r
n
a
l
s
.o
r
g
a
t
A
S
P
E
T
J
o
u
r
n
a
l
s
Fig.3. Structuresofnewmembersofthetraceaminefamily.Basedondemonstratedhigh-affinitybindingtoindividualTAARsandlowendogenous o
concentrations,thecompoundsshownareproposedasnewmembersforinclusioninthetraceaminefamily. n
M
a
r
c
h
1
3
, 2
0
2
3
TraceAminesandTheirReceptors 557
D
o
w
n
l
o
a
d
e
d
f
r
o
m
p
h
a
r
m
r
e
v
.a
s
p
e
t
j
o
u
r
n
a
l
s
.o
r
g
a
t
A
S
P
E
T
J
o
u
r
n
a
Fig.4. Endogenoussyntheticandmetabolicroutesfortraceamines.DBH,dopamine-b-hydroxylase;INMT,indolethylamineN-methyltransferase; ls
PAH,phenylalaninehydroxylase;TH,tyrosinehydroxylase. o
n
M
a
r
c
h
1
3
, 2
0
2
3
558 Gainetdinovetal.
1 and 2 within the 59-untranslated region has been phosphorylation sites (Hadjiconstantinou et al., 2010)
established as allowing for distinct control of neuronal or selective activation/inhibition of individual protein
andnon-neuronalexpression(Albertetal.,1992;Ichinose kinases (Young et al., 1993, 1994; Zhu et al., 1994;
etal.,1992;Hahnetal.,1993;Sumi-Ichinoseetal.,1995). Duchemin et al., 2000, 2010) alters AADC activity.
Avarietyoftranscriptionfactorbindingsiteshavebeen Direct evidence for phosphorylation of AADC by PKA
identifiedwithinboththeneuronal(Chireuxetal.,1994; (Duchemin et al., 2000) and protein kinase G
Aguannoetal.,1995)andnon-neuronal(Aguannoetal., (Duchemin et al., 2010) has been provided, although
1996) promoter regions through which tissue-selective PKC does not appear to directly increase phosphoryla-
expression could occur. A variant on this alternative tiondespitethepresenceofconsensusrecognitionsites
splicing,inwhichthenon-neuronalvariantwassplicedto (Ducheminetal.,2000).
theneuronalacceptorsite,hasalsobeensuggestedinG Intheretina,AADCactivityisincreasedinresponseto
cellsoftheratstomachantrum(Djalietal.,1998),which light(Hadjiconstantinouetal.,1988)orselectiveantag-
mayindicatecelltype–selectiveplasticityinthecontrolof onismofa -adrenergicreceptors(Rossettietal.,1989)or
2
AADC expression. Recently, a number of cis-acting D -likedopaminereceptors(D1Rs)(Rossettietal.,1990).
1
polymorphisms of AADC have been identified with Consistentwiththis,lightstresswasrecentlyreportedto
putative clinical relevance (Li and Meltzer, 2014; increaseretinalPEAlevels(delaBarcaetal.,2017).In
Eisenberg et al., 2016), and disease-associated AADC contrast, D1R agonists decrease both basal and light-
coding variants are also known (Graziano et al., 2015; induced AADC activity (Rossetti et al., 1990). Similar
Kojimaetal.,2016;Montiolietal.,2016). responses to dopamine receptor ligands have also been
The functional significance of alternative splicing observed in various rodent brain regions (Zhu et al.,
within the coding region of AADC is poorly defined. A 1992, 1993, 1994; Hadjiconstantinou et al., 1993; Cho
splice variant lacking exon 3 has been reported to be etal.,1997,1999;Neffetal.,2006).RegulationofAADC
widely expressed in both neuronal and non-neuronal by serotonergic receptors (Neff et al., 2006) and N-
tissue (O’Malley et al., 1995; Chang et al., 1996), with methyl-D-aspartate (NMDA) glutamatergic receptors
this shorter variant suggested to be devoid of both (Hadjiconstantinou et al., 1995; Fisher et al., 1998) has
L-DOPA and L-5-hydroxytryptophan decarboxylating alsobeenreported.ThereisalsosomeevidenceforAADC
activities(O’Malleyetal.,1995).Anevenshortervariant, regulation associated with systemic lupus erythemato-
lacking exons 11–15, has also been reported to be sus(Bengtssonetal.,2016),Parkinson’disease(Gjedde
expressed in non-neuronal tissues (Vassilacopoulou et al., 1993), and schizophrenia (Reith et al., 1994). In D
o
et al., 2004), although enzyme activity of this variant experimental animals, regulation of AADC after spinal w
was not examined. Additional coding splice variants cord injury has also been reported (Li et al., 2014; n
l
o
were also reported to be present in pancreatic b cells Wieneckeetal.,2014;Azametal.,2015). a
d
(Rorsmanetal.,1995),althoughagainthefunctionality In each of the above cases, the reported changes in e
d
of these putative alternative forms does not appear to AADC activity are normally rather modest (approxi- f
r
o
havebeenfurtherinvestigated.Whetheractivitytoward mately 30%) and insufficient to change endogenous m
substrates other than L-DOPA and L-5-hydroxytrypto- dopamine levels (Berry et al., 1994; Cho et al., 1999). ph
phan is lost, or even enhanced, is unknown, but the Suchtreatmentshave,however,beenshowntochange a
r
m
apparent widespread expression of an ostensibly non- both PEA and TYR levels (Juorio, 1979; Juorio et al.,
r
e
functional variant seems unlikely, and a role of one or 1991;Berry,2004)andcangenerallybesummarizedas v
.a
more splice variants in selective trace amine synthesis follows: treatments that increase monoamine neuro- s
p
couldprovideananswertothisparadox. transmitterreceptoractivationdecreasePEA/TYRsyn- e
t
j
Althoughitisnotarate-limitingstepinthesynthesis thesis, whereas treatments that decrease receptor o
u
of catecholamine and indoleamine neurotransmit- activationincreasePEA/TYRsynthesis.Inthisrespect, rn
a
ters under physiologic conditions, AADC activity is itisimportanttonotethatreportsofchangesinAADC ls
regulated in a biphasic manner. Both early changes, activityhavealmostexclusivelyusedonlyL-DOPAasa .or
g
consistent with alterations in phosphorylation status, substrate. Whether greater changes in the activity of a
t
and delayed, longer-lasting changes in enzyme expres- AADC toward other substrates (particularly L-phenyl- A
sion have been reported (Buckland et al., 1992, alanine, L-tyrosine, and/or L-tryptophan) occurs is un- SP
1996, 1997; Hadjiconstantinou et al., 1993; Berry known, although as described above there is evidence E
T
et al., 1996). Multiple consensus phosphorylation sites that substrate-dependent regulation of AADC is possi- J
o
for protein kinase A (PKA) (Young et al., 1993; ble(Rahmanetal.,1981;JuorioandYu,1985a,b;Siow u
r
Duchemin et al., 2000), protein kinase C (PKC) andDakshinamurti,1985).Kineticstudieshavereport- na
l
(Young et al., 1994; Zhu et al., 1994), protein kinase G edalterationsin AADC V inresponsetopharmaco- s
max o
(Duchemin et al., 2010), calmodulin-dependent kinase logical agents (Zhu et al., 1992; Young et al., 1994; n
M
II(Hadjiconstantinouetal.,2010),andproline-directed Duchemin et al., 2010) and both V and K in
max m a
kinase (Hadjiconstantinou et al., 2010) are present, response to site-directed mutagenesis of consensus rc
h
and both site-directed mutagenesis of individual phosphorylationsites(Hadjiconstantinouetal.,2010). 1
3
, 2
0
2
3