© 2018. Published by The Company of Biologists Ltd | Journal of Experimental Biology (2018) 221, jeb184838. doi:10.1242/jeb.
184838
REVIEW
Invertebrate serotonin receptors: a molecular perspective on
classification and pharmacology
Ann Jane Tierney*
ABSTRACT
Invertebrate receptors for the neurotransmitter serotonin (5-HT) have
been identified in numerous species from diverse phyla, including
Arthropoda, Mollusca, Nematoda and Platyhelminthes. For many
receptors, cloning and characterization in heterologous systems have
contributed data on molecular structure and function across both
closely and distantly related species. This article provides an
overview of heterologously expressed receptors, and considers
evolutionary relationships among them, classification based on
these relationships and nomenclature that reflects classification. In
addition, transduction pathways and pharmacological profiles are
compared across receptor subtypes and species. Previous work has
shown that transduction mechanisms are well conserved within
receptor subtypes, but responses to drugs are complex. A few ligands
display specificity for different receptors within a single species;
however, none acts with high specificity in receptors across different
species. Two non-selective vertebrate ligands, the agonist 5-
methoxytryptamine and antagonist methiothepin, are active in
most receptor subtypes in multiple species and hence bind very
generally to invertebrate 5-HT receptors. Future challenges for the
field include determining how pharmacological profiles are affected
by differences in species and receptor subtype, and how function in
heterologous receptors can be used to better understand 5-HT
activity in intact organisms.
KEY WORDS: 5-Hydroxytryptamine, 5-HT, G-protein-coupled
receptor, Insect, Nematode
Introduction
Serotonin (5-hydroxytryptamine, 5-HT; see Glossary) and its
receptors (see Glossary) form one of the oldest and most widely
distributed signalling systems found in nature. An extended period
of evolution, unfolding over an estimated 750 million years, has
yielded an array of 5-HT receptors mediating myriad functions. In
vertebrates, 5-HT acts as a central nervous system (CNS) transmitter
and modulator, and its role in mood, cognitive processes and
numerous behaviours is well documented. 5-HT and its receptors
are the focus of much effort to understand psychological disorders
in humans and to identify new pharmaceutical treatments (Hoyer
et al., 2002; Pithadia and Jain, 2009; Nautiyal and Hen, 2017). In
addition to its actions in the CNS, 5-HT is important throughout the
body, modulating function in all physiological systems in adulthood
and during development. 5-HT is likewise important in invertebrate
behaviour and physiology (Gillette, 2006; Blenau and Thamm,
2011; Wu and Cooper, 2012). The study of 5-HT in diverse
Neuroscience Program, Department of Psychology, Colgate University, Hamilton,
NY 13346, USA.
*Author for correspondence (atierney@colgate.edu)
A.J.T., 0000-0003-0979-5885
invertebrates has contributed insight into the evolutionary and
molecular underpinnings of this ubiquitous signalling system.
Many experiments address serotonergic function (see Glossary) in
model organisms which are important for elucidating general
principles relevant to human biology and health.
In mammals, seven 5-HT receptor families (5-HT1 to 5-HT7)
have been identified comprising 14 receptors, 13 of which are G-
protein coupled and one of which (5-HT3) is ionotropic (see
Glossary). According to estimates, the major 5-HT G-protein-
coupled receptor families differentiated prior to the separation of
vertebrates and invertebrates 600 million years ago, and hence the
same major receptor families are thought to exist in the two
groups (Peroutka and Howell, 1994; Walker et al., 1996). During
subsequent vertebrate evolution, further differentiation occurred
within some receptor families, yielding five 5-HT1 (5-HT1A, 5-
HT1B, 5-HT1D, 5-HT1E, 5-HT1F), three 5-HT2 (5-HT2A, 5-HT2B,
5-HT2C) and two 5-HT5 (5-HT5A, 5-HT5B) receptors. The
receptor families, which are recognized based on gene
organization and sequence homology, can also be grouped by
their primary transduction mechanism (Nichols and Nichols, 2008).
5-HT1 and 5-HT5 couple preferentially to Gi/o proteins, leading to
decreased production of cAMP, whereas 5-HT4, 5-HT6 and 5-HT7
couple preferentially to Gs proteins, leading to increased cAMP
production. 5-HT2 receptors couple to Gq proteins, inducing
elevated Ca2+ levels (Fig. 1). The mammalian receptors display
different responses to agonist and antagonist drugs, and hence they
can also be recognized by pharmacological properties (Hoyer et al.,
2002; Pytliak et al., 2011).
In invertebrates, early molecular studies confirmed the presence of
5-HT receptor genes orthologous to mammalian 5-HT1, 5-HT2 and
5-HT7, as determined by similarities in sequence and transduction
mechanisms (Tierney, 2001). The first invertebrate receptor cloned,
5-HT-dro1 (Witz et al., 1990) later termed 5-HT7Dro (Colas et al.,
1995), was also the first 5-HT7 receptor to be discovered; the
mammalian 5-HT7 receptor was subsequently cloned and found to be
Journal of Experimental Biology
homologous (see Glossary) to 5-HT7Dro (Shen et al., 1993; Bard et al.,
1993). 5-HT1 receptors were discovered next, first in Drosophila
(Saudou et al., 1992) and then in other insects (Von Nickisch-
Rosenegk et al., 1996), gastropods (Mollusca, see Glossary)
(Sugamori et al., 1993; Angers et al., 1998) and Caenorhabditis
elegans (Nematoda, see Glossary) (Olde and McCombie, 1997). Early
studies also demonstrated the presence of 5-HT2 receptors in
Drosophila (Colas et al., 1995), molluscs (Gerhardt et al., 1996)
and nematodes (Hamdan et al., 1999; Huang et al., 1999). The
preferential G-proteins mediating transduction were Gs, Gi and Gq for
5-HT7, 5-HT1 and 5-HT2, respectively, indicating conservation with
mammalian receptors in each class.
Since the 1990s, researchers have cloned numerous additional
invertebrate 5-HT receptors, providing new data on gene structure,
transduction mechanisms and pharmacology. Here, I review this
information and, based on the proposed evolutionary relationships,
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Glossary
Arthropoda
A large phylum that includes insects, arachnids, crustaceans and
myriapods.
Cys-loop
A superfamily of ionotropic receptors that share a common molecular
structure consisting of five subunits surrounding a central ion-conducting
pore.
Expression
To ‘express’ a gene that codes for a protein receptor is to cause it to be
transcribed, translated and situated in a host cell membrane where it can
exhibit functional properties.
Heterologous expression
Use of recombinant DNA techniques to express a gene from one species
in a cell or organism of a different species.
Homologous
Genes are homologous if they are related to each other as a result of
descent from a common ancestral gene.
Host cell (or host organism)
The cell or organism used to express a foreign protein; also called an
‘expression system’.
Inverse agonist
A ligand that binds to a receptor and produces an effect opposite to that
produced by the endogenous ligand.
Ionotropic
An ion channel protein that changes conformation upon the binding of a
ligand and allows ions to pass across the membrane; examples include
the nicotinic ACh receptor, the GABAA receptor and 5-HT3.
Mollusca
A diverse phylum that includes gastropods (e.g. snails), bivalves (e.g.
clams) and cephalopods (e.g. squid).
Nematoda
This phylum contains the roundworms and includes both free-living and
parasitic species; the model species Caenorhabditis elegans belongs to
this phylum.
Orthologue
Homologous genes in different species in which sequence divergence
occurs after a speciation event.
Paralogue
Homologous genes in a single or multiple species in which sequence
divergence occurs after a duplication event.
Platyhelminthes
This phylum includes Cestodes (tapeworms) and Trematodes (flukes)
and contains both free-living and parasitic species.
Receptor
Protein located on the surface of a cell that binds ligands such as
neurotransmitters and hormones.
RNAi knockdown
This technique uses RNA interference (RNAi) to inactivate messenger
RNA (mRNA) for a particular gene to effectively suppress (or
knockdown) expression of the gene.
Serotonergic
Processes or agents that involve serotonin, serotonin receptors or
serotonin synapses.
Serotonin
A widely distributed monoamine that functions as a neurotransmitter
and a chemical messenger molecule throughout the body; also called
5-hydroxytryptamine (5-HT) or enteramine.
Transduction pathway
A sequence of biochemical events triggered by the binding of a molecule
(e.g. serotonin) to a receptor, resulting in the production of a second
messenger (e.g. cAMP) that affects processes within a cell or at the
plasma membrane.
consider the classification of invertebrate receptors.
Pharmacological profiles are summarized, with the aim of
identifying ligands that can be used to define receptor subtypes or
be useful in investigations of receptors in native tissue. However,
Journal of Experimental Biology (2018) 221, jeb184838. doi:10.1242/jeb.184838
comparisons among invertebrate receptors are hampered by the lack
of a common nomenclature. Names currently assigned to the
growing number of invertebrate receptors are highly variable and
often do not reflect receptor relationships. Mammalian researchers
confronted a similar problem in the 1980s when the historical order
of receptor discovery and characterization led to labelling that was
irregular and confusing. This problem was addressed by the
IUPHAR Receptor Nomenclature Committee, which proposed a
standardized way to name receptors and provided updates to
accommodate new findings (Humphrey et al., 1993; Hoyer, 2017).
Invertebrate 5-HT receptors await a similar collaborative effort. In
the meantime, this paper follows the customary nomenclature used
for vertebrates that recognizes proposed evolutionary and functional
relationships among receptors.
Nomenclature and receptor classification
The nomenclature used to identify vertebrate receptors indicates the
relevant endogenous ligand first, followed by a numbered subscript
to indicate the receptor class. For invertebrate 5-HT receptors (e.g.
5-HT1, 5-HT2, 5-HT7), these subscripts indicate proposed
homology with mammalian receptor families. Species
identification is important as invertebrate 5-HT receptors can be
expected to vary significantly owing to the long periods of
independent evolution in different phyla. Where relevant for
mammalian receptors, species is denoted by a single letter, e.g. h
5-HT7 and r 5-HT7 for human and rat receptors, respectively
(Vanhoutte et al., 1996). However, invertebrate receptors have not
traditionally been identified in this manner and a single letter for a
common name provides insufficient information for invertebrate
species identification. Here, species is indicated by the first three
letters of the genus in the subscript (e.g. 5-HT1Apl to denote an
Aplysia receptor); if these letters provide insufficient information for
species identification, the first two letters of a species name are
added (e.g. 5-HT1Aplca to denote an Aplysia californica receptor).
The expansion of knowledge of invertebrate receptors from diverse
phyla presents additional and significant challenges for the
development of precise nomenclature. Ideally, receptors should be
labelled in a manner that illuminates proposed orthologous
relationships among receptors and precisely identifies genes that
differ as a result of recent duplications or alternative splicing. In
mammalian 5-HT receptor nomenclature, the uppercase letters that
follow subscript numbers indicate different genes within a receptor
family (e.g. 5-HT1A, 5-HT1B, 5-HT1D) and orthologues (see Glossary)
across different species (e.g. the h 5-HT1B receptor is orthologous to
the r 5-HT1B receptor). However, letters associated with invertebrate
5-HT receptor subscripts do not signify orthology to vertebrate
Journal of Experimental Biology
receptor subtypes as the latter emerged after the evolutionary
separation of vertebrates and invertebrates (Peroutka and Howell,
1994). Also, additional uppercase, lowercase and Greek letters or
numbers have been applied inconsistently and do not unequivocally
characterize evolutionary relationships among invertebrate receptor
genes or identify isoforms of the same gene. In this review, we follow
researchers (Clark et al., 2004; Thamm et al., 2013) who have used
Greek letters, α and β, to identify different genes within receptor
families, thereby avoiding the implication of orthology with well-
established mammalian receptor subtypes. If paralogues (see
Glossary), arising owing to recent gene duplication events, exist
within a receptor subtype, they are identified by lowercase letters (e.g.
5-HT1αa and 5-HT1αb). Multiple genes within the 5-HT7 receptor
family are likewise distinguished by lowercase letters pending
additional information on the evolutionary origins of these genes.
Different sequences identified as functional splice variants are
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5-HT

5-HT4/6/7 5-HT1/5 5-HT2

Membrane

s   
AC i PLC q
Cytoplasm   

Activation Inhibition Activation

Decrease in cAMP IP3 Increase in Ca2+

Increase in cAMP

Fig. 1. Schematic diagram illustrating 5-HT receptors and their simplified transduction pathways. The receptors depicted are proteins with seven
transmembrane α-helixes (blue), a molecular structure shared by all members of the G-protein-coupled receptor (GPCR) superfamily. The receptors bind 5-HT
and other ligands on their extracellular side and contain a binding site for G-proteins on the cytoplasmic side. G-proteins are trimeric structures comprising α, β and
γ subunits, each encoded by multiple genes. The binding of 5-HT induces a conformational change in the receptor which activates G-proteins. Activated G-
proteins interact with effector proteins, including the enzymes adenylate cyclase (AC) and phospholipase C (PLC), to transduce cellular responses. In both
vertebrates and invertebrates, 5-HT receptors can be grouped by their primary transduction mechanism. 5-HT4/6/7 receptors bind G-proteins containing αs
subunits, which activate AC, resulting in the production of the second messenger cAMP. 5-HT1/5 receptors bind G-proteins containing αi/o subunits, which inhibit
AC, resulting in a decrease in intracellular cAMP. 5-HT2 receptors are linked to G-proteins of the αq family, which activate PLC, resulting in the production of
second messengers, including inositol 1,4,5-trisphosphate (IP3). IP3 stimulates the release of Ca2+ from intracellular organelles, leading to an increase in Ca2+ in
the cytoplasm. Changes in intracellular cAMP or Ca2+ levels affect numerous cellular processes and regulate gene expression. Experimentally, changes in cAMP
and Ca2+, or processes dependent on these second messengers, can be measured to functionally characterize 5-HT receptors expressed in heterologous
systems (Table S1).

identified by lowercase letters in parentheses (e.g. 5-HT2(a) and 5-
HT2(b)). Names used in this paper according to the above criteria are
specified in Table 1. Note that this table includes receptors with known
functional properties, and is not intended to provide an exhaustive
catalogue of all possible or putative 5-HT receptors.
Unlike mammalian receptors, which come from a single class of
organisms, invertebrate receptors are from multiple classes and
distantly related phyla. Hence, orthologous relationships within
receptor families may occur within phyla, but not necessarily across
phyla. The classification of 5-HT receptors described below and
depicted in Table 1 is provisional and will be subjected to revision
as knowledge of invertebrate receptors expands and evolutionary
relationships are further elucidated. At the present time, two 5-HT1
subtypes have been distinguished in species from the phylum
Arthropoda (see Glossary): 5-HT1α and 5-HT1β. The gene
duplication that formed these subtypes is proposed to have taken
place prior to the separation of insects and crustaceans, and hence α
and β subscripts represent orthologues within this group of animals
(Dacks et al., 2006; Watanabe et al., 2011). The prototypical
distinct genes appear to exist. Barbas et al. (2002) described a
receptor in A. californica that differed from the 5HT1 receptor
previously described by Angers et al. (1998), and that more closely
resembled the sequence from the 5-HT1 receptor (5-HT1Lym) from
Lymnaea stagnalis (Sugamori et al., 1993). Phylogenetic analyses
(Mapara et al., 2008; Panasophonkul et al., 2009; Tanabe et al.,
2010) indicate that additional molluscan 5-HT1 receptors listed in
Table 1 are also more closely related to 5-HT1Lym than to the first
receptor cloned from Aplysia (Angers et al., 1998), and the latter
may derive from a recent gene duplication (Nagakura et al., 2010). It
would be premature to delineate receptor subtypes in molluscs, and
hence Greek letters were not applied and the two Aplysia receptors
are distinguished by lowercase letters. Two previously described
Aplysia receptors are not listed because they are no longer
definitively identified as 5-HT receptors (Li et al., 1995, 2003).
Thus far, two 5-HT1 receptors have been characterized in nematodes
(Olde and McCombie, 1997; Smith et al., 2003) and are classified
by a number subscript only.
5-HT2 receptors are also divided into two subtypes in arthropods:

Journal of Experimental Biology

separation of the Drosophila 5-HT1 receptor gene into two genes
labelled A and B (5-HT-dro2A and 5-HT-dro2B later termed 5-
HT1ADro and 5-HT1BDro, respectively; Saudou et al., 1992) does not
reflect the current classification of 5-HT1 receptor subtypes.
Instead, most phylogenetic analyses place both of these genes in the α
subgroup (Troppmann et al., 2010; Qi et al., 2017), suggesting a recent
duplication event in Drosophila (Watanabe et al., 2011). The two
genes are therefore identified as 5-HT1αaDro and 5-HT1αbDro. At the
present time, most insect receptors fall into the 1α clade, as do 5-HT1
receptors from crustaceans and the tick Boophilus microplus (Table 1);
four 1β receptors have been identified from the moths Bombyx mori
(Von Nickisch-Rosenegk et al., 1996) and Manduca sexta (Dacks
et al., 2006), the field cricket Gryllus bimaculatus (Watanabe et al.,
2011) and the butterfly Pieris rapae (Qi et al., 2017).
In other phyla, fewer 5-HT1 receptors have been characterized
and subtypes have not yet been defined. In molluscs, however, two
5-HT2α and 5-HT2β. The first receptor, cloned by Colas et al. (1995)
from Drosophila, is currently considered a member of the 5-HT2α
group. Orthologous 2α receptors have been characterized in
G. bimaculatus (Watanabe et al., 2011), the blowfly Calliphora
vicina (Röser et al., 2012), M. sexta (Dacks et al., 2013) and the
honeybee Apis mellifera (Thamm et al., 2013). A second 5-HT2
sequence was reported in Drosophila (Brody and Cravchik, 2000;
Clark et al., 2004) and later cloned and characterized by Gasque and
colleagues (2013); it was named 5-HT2βDro (Clark et al., 2004) or
5-HT2B (Gasque et al., 2013). Orthologous 5-HT2β receptors have
been described in G. bimaculatus (Watanabe and Aonuma, 2012),
A. mellifera (Thamm et al., 2013), the insect Rhodnius prolixus
(Paluzzi et al., 2015) and the crustaceans Panulirus interruptus
(Clark et al., 2004), Procambarus clarkii (Spitzer et al., 2008) and
Macrobrachium rosenbergii (Vázquez-Acevedo et al., 2009). The
5-HT2 receptors characterized in molluscs (Gerhardt et al., 1996;

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Table 1. Invertebrate 5-HT receptors organized by receptor subtype

Previous name(s) Revised name Accession no. Species Reference
5-HT1-like receptors
Arthropoda, Insecta
5-HT-dro2A, 5-HT1Adro 5-HT1αaDro Z11489 Drosophila melanogaster Saudou et al., 1992
5-HT-dro2B, 5-HT1Bdro 5-HT1αbDro Z11490 Drosophila melanogaster Saudou et al., 1992
K15Hel 5-HT1αHelvi X95605 Heliothis virescens Von Nickisch-Rosenegk et al., 1996
Px5HT1 5-HT1αPap AB182632 Papilio xuthus Ono and Yoshikawa, 2004
Ms5HT1A 5-HT1αMan DQ840515 Manduca sexta Dacks et al., 2006
Am5-HT1A 5-HT1αApi FN645449 Apis mellifera Thamm et al., 2010
Pea5-HT1 5-HT1αPer FN298392 Periplaneta americana Troppmann et al., 2010
5-HT1A 5-HT1αGry AB618098 Gryllus bimaculatus Watanabe et al., 2011
Trica5-HT1 5-HT1αTri KC196076 Tribolium castaneum Vleugels et al., 2013
Piera5-HT1A 5-HT1αPie KT946786 Pieris rapae Qi et al., 2017
B150Bom 5-HT1βBom X95604 Bombyx mori Von Nickisch-Rosenegk et al., 1996
Ms5HT1B 5-HT1βMan DQ840516 Manduca sexta Dacks et al., 2006
5-HT1B 5-HT1βGry AB618099 Gryllus bimaculatus Watanabe et al., 2011
Piera5-HT1B 5-HT1βPie KT946787 Pieris rapae Qi et al., 2017
Arthropoda, Malacostraca
5-HT1Mac 5-HT1αMac AY528821 Macrobrachium rosenbergii Sosa et al., 2004
EU363466 Vázquez-Acevedo et al., 2009
5-HT1Pan 5-HT1αPan AY528822 Panulirus interruptus Sosa et al., 2004
Spitzer et al., 2008
5-HT1Pem 5-HT1αPen AY661549 Penaeus monodon Ongvarrasopone et al., 2006
5-HT1αPro 5-HT1αPro EU131667 Procambarus clarkii Spitzer et al., 2008
Arthropoda, Arachnida
5-HT1 5-HT1αBoo AY323235 Boophilus microplus Chen et al., 2004
Mollusca, Gastropoda
5HTlym 5-HT1Lym L06803 Lymnaea stagnalis Sugamori et al., 1993
5-HTap1 5-HT1aAplca AF041039 Aplysia californica Angers et al., 1998
5-HTap2 5-HT1bAplca AF372526 Aplysia californica Barbas et al., 2002
5-HT1Hel 5-HT1Heltr AY395746 Helisoma trivolvis Mapara et al., 2008
5-HT1ha 5-HT1Hal EU342382 Haliotis asinina Panasophonkul et al., 2009
Mollusca, Bivalvia
5-HTpy 5-HT1Pat AB209935 Patinopecten yessoensis Tanabe et al., 2010
5-HTpf 5-HT1Pin KF954511 Pinctada fucata Wang and He, 2014
Nematoda, Chromadorea
5-HT-Ce 5-HT1Cae U15167 Caenorhabditis elegans Olde and McCombie, 1997
5-HT1ce, SER-4
Nematoda, Secernentea
5-HT1Hc 5-HT1Hae AY204355 Haemonchus contortus Smith et al., 2003
5-HT2-like receptors
Arthropoda, Insecta
5-HT2Dro 5-HT2αDro X81835 Drosophila melanogaster Colas et al., 1995
5-HT2α 5-HT2αGry AB618100 Gryllus bimaculatus Watanabe et al., 2011
Cv5-HT2α 5-HT2αCal HE657271 Calliphora vicina Röser et al., 2012
Am5-HT2α 5-HT2αApi FR727107 Apis mellifera Thamm et al., 2013
Ms5HT2 5-HT2αMan JX891652 Manduca sexta Dacks et al., 2013
Dm5-HT2B 5-HT2βDro CG8007/CG42796 Drosophila melanogaster Brody and Cravchik, 2000
Gasque et al., 2013
5-HT2β 5-HT2βGry AB667995 Gryllus bimaculatus Watanabe and Aonuma, 2012
Am5-HT2β 5-HT2βApi FR727108 Apis mellifera Thamm et al., 2013

Journal of Experimental Biology

Rhopr5HTR2b 5-HT2βRho KP325472 Rhodnius prolixus Paluzzi et al., 2015
Arthropoda, Malacostraca
5-HT2βPan 5-HT2βPan AY550910 Panulirus interruptus Clark et al., 2004
5-HT2βPro 5-HT2βPro EU131666 Procambarus clarkii Spitzer et al., 2008
5-HT2Mac 5-HT2βMac EF033662 Macrobrachium rosenbergii Vázquez-Acevedo et al., 2009
Mollusca, Gastropoda
5-HT2Lym 5-HT2Lym U50080 Lymnaea stagnalis Gerhardt et al., 1996
5-HT2Apl 5-HT2Aplca HM187583 Aplysia californica Nagakura et al., 2010
Nematoda, Chromadorea
5-HT2CeL, SER-1 5-HT2(a)Cae AF031414 Caenorhabditis elegans Hamdan et al., 1999
5-HT2CeS, SER-1 5-HT2(b)Cae AF031415 Caenorhabditis elegans Hamdan et al., 1999
AS1, 5-HTAsc 5-HT2Asc AF005486 Ascaris suum Huang et al., 1999
5-HT4- and 5-HT6-like receptors
Mollusca, Gastropoda
5HT4Apl 5HT4Apl HM187584 Aplysia californica Nagakura et al., 2010
Nematoda, Chromadorea
SER-5 5-HT6Cea F16D3.7 Caenorhabditis elegans Hapiak et al., 2009
Continued

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Table 1. Continued
Previous name(s) Revised name Accession no. Species Reference
5-HT7-like receptors
Arthropoda, Insecta
5-HTdro1 5-HT7Dro M55533 Drosophila melanogaster Witz et al., 1990
Aedes 5-HT7 5-HT7Aed AF296125 Aedes aegypti Pietrantonio et al., 2001
Am5-HT7 5-HT7Api AM076717 Apis mellifera Schlenstedt et al., 2006
5-HT7 5-HT7Gry AB618101 Gryllus bimaculatus Watanabe et al., 2011
Cv5-HT7 5-HT7Cal HE657272 Calliphora vicina Röser et al., 2012
Ms5HT7 5-HT7Man JX878498 Manduca sexta Dacks et al., 2013
Trica5-HT7 5-HT7Tri XP_966577 Tribolium castaneum Vleugels et al., 2014
Piera5-HT7 5-HT7Pie KT946790 Pieris rapae Qi et al., 2017
Mollusca, Gastropoda
5-HT7Hel 5-HT7Heltr AY395747 Helisoma trivolis Mapara et al., 2008
5-HTapAC1 5-HT7Aplku FJ477896 Aplysia kurodai Lee et al., 2009
Nematoda, Chromadorea
SER-7b 5-HT7Cae NM171637 Caenorhabditis elegans Hobson et al., 2003
Platyhelminthes, Rhabditophora
5HTLpla4, S7.1R 5-HT7aDug AB004540 Dugesia japonica Saitoh et al., 1997
5HTLpla1 5-HT7bDug AB004541 Dugesia japonica Saitoh et al., 1997
DjSER-7 5-HT7cDug AB495373 Dugesia japonica Nishimura et al., 2009
Platyhelminthes, Trematoda
Sm5HTR 5-HT7aSch KF444051 Schistosoma mansoni Patocka et al., 2014
Sm5HTRL 5-HT7bSch KX150867 Schistosoma mansoni Chan et al., 2016b
Platyhelminthes, Cestoda
5-HT7Egran1 5-HT7aEch MH707372 Echinococcus granulosus Camicia et al., 2018
5-HT7Egran2 5-HT7bEch MH707373 Echinococcus granulosus Camicia et al., 2018
5-HT7Mco1 5-HT7Mes MH707374 Mesocestoides corti Camicia et al., 2018
Additional receptors
Pr5-HT8 5-HT8Pie KF878930 Pieris rapae Qi et al., 2014
MOD-1 MOD-1 Q9GQ00 Caenorhabditis elegans Ranganathan et al., 2000
Hco-MOD-1 Hco-MOD-1 HM219644 Haemonchus contortus Beech et al., 2013
Names previously assigned and revised nomenclature used in this review are noted for each receptor.

Nagakura et al., 2010) and nematodes (Hamdan et al., 1999; Huang
et al., 1999, 2002) are identified by number subscripts only.
Receptor subtypes in these groups have not yet been described,
although functional splice variants have been shown to occur in
both nematode species.
In both mammals and invertebrates, the 5-HT4, 5-HT6 and 5-HT7
receptors each comprise a single subtype (Hoyer et al., 2002;
Nichols and Nichols, 2008) and are identified by a subscript
number. Few 5-HT4 and 5-HT6 receptors have been reported in
invertebrates. However, these receptors do occur as a 5-HT4 and a
5-HT6 receptor were identified in Aplysia (Nagakura et al., 2010)
and C. elegans (Carre-Pierrat et al., 2006; Hapiak et al., 2009),
respectively. By contrast, 5-HT7 receptors occur widely and have
been characterized in a number of insects, gastropod molluscs, and
C. elegans (Table 1). In addition, 5-HT7 receptors have been
all belong to the Cys-loop receptor superfamily (see Glossary),
which includes the mammalian 5-HT3 receptor. While MOD-1 and
5-HT3 share a distant evolutionary past and gating by 5-HT, they
differ in function in that MOD-1 is a chloride channel whereas 5-
HT3 is a non-selective cation channel (Yaakob et al., 2018).
MOD-1 is important in C. elegans, contributing to the control of
behaviours such as locomotion, feeding, decision making and
aversive learning (Churgin et al., 2017; Iwanir et al., 2016; Zhang
et al., 2005). This receptor also occurs in the parasitic nematode
Haemonchus contortus and is predicted to be present in several
additional nematodes (Komuniecki et al., 2012; Beech et al., 2013),
but it has not been reported in other invertebrate clades. In the
butterfly P. rapae, a novel receptor has been described by Qi et al.
(2014) that is proposed to belong to a new family of receptors
designated 5-HT8. 5-HT activation of this receptor in HEK293 cells

Journal of Experimental Biology

described in flatworms ( phylum Platyhelminthes; see Glossary),
and this receptor family appears to be the dominant clade in these
organisms. Multiple sequences have been found in the planarian
Dugesia japonica (Saitoh et al., 1997; Nishimura et al., 2009), the
parasitic worm Schistosoma mansoni (Patocka et al., 2014; Chan
et al., 2016a) and the cestodes Echinococcus granulosus and
Mesocestoides corti (Camicia et al., 2018). Genome searches
predict the presence of additional 5-HT receptors in Platyhelminthes
(Chan et al., 2015; Patocka et al., 2014), but they have not yet been
characterized. Patocka et al. (2014) was unable to find 5-HT2
receptors in S. mansoni and suggested that they may have been lost
in this organism or in the phylum.
An additional receptor, MOD-1, is a serotonin-gated ion channel
found in C. elegans with a predicted protein structure similar to that
of ionotropic receptors gated by acetylcholine, GABA, glycine and
5-HT (Ranganathan et al., 2000). These ligand-gated ion channels
induced an increase in Ca2+, but the sequence and pharmacology do
not resemble 5-HT2 or other insect 5-HT receptors. Further research
is needed to confirm whether 5-HT is the endogenous ligand and to
characterize the receptor in additional species.
Pharmacology
It has been clear for many years that responses to serotonergic drugs
differ between invertebrate and mammalian receptors (Tierney,
2001). Given the substantial increase in characterized invertebrate
receptors, it is timely to consider how pharmacology varies within
and between invertebrate phyla themselves. The heterologous
expression (see Glossary) of cloned receptors has offered much
valuable information on the pharmacology of receptors definitively
identified at the molecular level. However, interpretation of data and
comparisons across receptor subtypes and species are complex for
several reasons. First, researchers use a variety of host cells (see

5
REVIEW Journal of Experimental Biology (2018) 221, jeb184838. doi:10.1242/jeb.184838

Glossary), each of which possesses its own regulatory mechanisms

and membrane environment, potentially affecting the methodology
required for expression (see Glossary), receptor structure and S
Jo S
receptor–ligand interactions (Kenakin, 1997; Thomas and Smart,
2005). Thus, the same receptor might function differently
ur
depending on the expression system used or in comparison with H na
N
H l
the endogenous receptor in native tissue. Second, different assays O
are used to determine pharmacological properties, including 2 of
Ser
outcomes of transduction pathways (see Glossary), inhibition of
radioligand binding and changes in ion currents. Different assays
H Ex
oton
in N
yield disparate information on drug potency and efficacy, limiting pe
(5-
direct and quantitative comparisons of drug effects. Third, the ri
HT)
H
N m
battery of drugs tested varies from experiment to experiment, and
3
few drugs have been tested in multiple receptor subtypes. Finally,
the heterologous expression of receptors and screening of many
H
C en
O N
2
drugs is a lengthy process, and detailed data on receptor
5-
M
ta
pharmacology are available for relatively few species. Hence, it is et l
difficult to discern whether differences in receptor responses arise H h
o
Bi
from species differences, structural differences among receptor
x O ol
subtypes or artifacts of methodologies used. Despite these caveats, H
the information acquired by research to date provides a useful guide
yt
ry 2 og
for future studies and allows some preliminary conclusions to be pt N y
NH2
drawn. a
To characterize receptor subtypes across species, it is essential N m H
that the same drugs be tested on multiple organisms. In the in 5
arthropod 5-HT1 receptor, this has been achieved with several e NH-2
C
agonists, including 5-MeOT, 5-CT, 2-methyl-5-HT, α-methyl-5-HT H a
2
O
and 8-OH-DPAT (Table S1; Fig. 2). 5-MeOT, a non-selective - r
vertebrate 5-HT receptor agonist, elicited responses across all M b
CH3 o
receptors tested (5-HT1αMan, 5-HT1βMan, 5-HT1αApi, 5-HT1αPer, 5- et

N
h x
HT1αPie, 5-HT1βPie and 5-HT1αPan). 5-CT is also a non-selective a
agonist with high affinity for vertebrate 5-HT1/5/7 receptors. It had yl
- mN
variable effects at arthropod 5-HT1 receptors, displaying activity at M 5 i
some receptors (5-HT1αApi, 5-HT1αTri and 5-HT1αPan) and weak or et - d
no activity at others (5-HT1αMan, 5-HT1βMan, 5-HT1αPer, 5-HT1αPie hi H o
ot T t CH3
and 5-HT1βPie). Likewise, the actions of both 2-methyl-5-HT and h r
α-methyl-5-HT were variable, but one or both displayed relatively e y
high potency at certain receptors (5-HT1αTri, 5-HT1αPan and 5- pi p
HT1αPro). 8-OH-DPAT is a well-known agonist at the vertebrate 5- n t
H a
HT1A receptor, but it had low potency or was completely
m
ineffective in all of the arthropod 5-HT1 receptors. Interestingly, i CH3
methysergide is an antagonist at vertebrate and Drosophila 5-HT n
receptors (Saudou et al., 1992), but displayed agonist activity in M e
several receptors (Table S1). The most commonly tested antagonists ia
n
were methiothepin (Fig. 2), which is non-selective at vertebrate s
receptors, and WAY 100635, a vertebrate 5-HT1A antagonist. er
Methiothepin was a relatively potent antagonist in most arthropod in
receptors tested (5-HT1βMan, 5-HT1αApi, 5-HT1αPer, 5-HT1αTri, 5- Fig. 2. Molecular structure of 5-HT and 5-HT receptor ligands. Displayed
HT1αPie and 5-HT1βPie). WAY 100635 was an active antagonist in are the structures of 5-HT and several ligands which act as non-specific
several receptors (5-HT1αMan, 5-HT1βMan and 5-HT1αTri) and acted agonists (5-methoxytryptamine, 5-carboxamidotryptamine, 2-methyl-5-HT)
as an inverse agonist (see Glossary) at 5-HT1αPer. and non-specific antagonists (methiothepin and mianserin) at invertebrate
5-HT receptors.
Results thus far allow very limited comparisons between 5-HT1α
or 5-HT1β receptors across species. However, within species, Dacks
et al. (2013) reported that methiothepin was an antagonist at 5- receptors in each species. In addition, quipazine was an agonist at
HT1βMan receptors, but had no activity at 5-HT1αMan receptors, and 5-HT1αPro receptors, but inactive at 5-HT2βPro receptors (Spitzer
Qi et al. (2017) found that 8-OH-DPAT at high concentrations had et al., 2008).
greater efficacy at 5-HT1αPie than at 5-HT1βPie. Within-species In molluscs, pharmacological profiles are available for 5-HT1
comparisons also point to possible drug specificity across other receptors from Lymnaea (5-HT1Lym) and Aplysia (5-HT1aAplca and
receptor families. For example, methysergide acted as an agonist at 5-HT1bAplca), and they display notable consistency between the two
5-HT1αMan (and 5-HT7Man) receptors, but was inactive at 5-HT2αMan species (Table S1). 5-CT and PAPP were relatively potent agonists
receptors (Dacks et al., 2013). In crustaceans, mCPP was an agonist at all three receptors, whereas 8-OH-DPAT and NAN-190 were
of 5-HT1αPro and 5-HT1αPan receptors, but inactive at 5-HT2β less potent. Methiothepin was the most potent antagonist, and

6
REVIEW
metergoline also displayed high potency in all three receptors.
The molluscan profiles resemble those of arthropods in that
methiothepin displays high affinity for all three receptors, but the
response to agonists is quite different, with 5-CT and 8-OH-DPAT
displaying greater potency at molluscan compared with arthropod
receptors. Another difference between the two groups lies in the
relative potency of 5-HT. In arthropods, 5-HT is typically much
more potent and effective than synthetic ligands (Vleugels et al.,
2015), but in molluscan 5-HT1 receptors this is not the case as
several drugs act much more potently than does 5-HT itself.
Only two nematode 5-HT1 receptors have been examined
pharmacologically: 5-HT1Cae and 5-HT1Hae. Ligands shown to be
active in both receptors included lisuride, 5-OMeDMT,
methiothepin, methysergide and clozapine, but affinity for the
chemicals differed considerably. 5-HT1Cae resembled the molluscan
5-HT1 receptors in that 5-HT displayed less affinity than many
synthetic drugs (Olde and McCombie, 1997). However, affinity for
5-HT was much higher at 5-HT1Hae than at 5-HT1Cae, and only a
single drug (PAPP) displayed slightly higher affinity than 5-HT
(Smith et al., 2003).
The pharmacology of arthropod 5-HT2 receptors has been
examined in four 5-HT2α and five 5-HT2β receptors. Agonists
displaying activity in multiple receptors resembled the previous
list for 5-HT1 receptors: 5-MeOT, 8-OH-DPAT, α-methyl-5-HT,
2-methyl-5-HT and 5-CT (Table S1). The affinity or rank order
of potency varied among species, but none acted with sufficient
specificity to distinguish 5-HT2α from 5-HT2β receptors or to
distinguish either from receptors in other families. Among
antagonists, methiothepin was active at 5-HT2αDro, 5-HT2βDro, 5-
HT2αCal, 5-HT2αApi, 5HT2βPro and 5HT2βPan receptors, confirming
its status as a non-selective antagonist. Mianserin and
cyproheptadine, vertebrate 5-HT2 antagonists, were active in all
receptors tested (5-HT2αDro, 5-HT2αCal, 5-HT2αApi, 5-HT2βApi, 5-
HT2βRho and 5-HT2βDro), and additional antagonists (clozapine,
yohimbine, ketanserin, methysergide and spiperone) had variable
effects among 5-HT2α/β receptors. Limited testing suggests that
these antagonists were also active at some 5-HT1 and 5-HT7
receptors, indicating that they lack specificity across species.
However, within species, some drugs displayed actions that point
to a selectivity that would be useful to examine in other species. In
A. mellifera, Thamm et al. (2013) reported that SB-200646,
methiothepin and methysergide displayed high potency at 5-
HT2αApi receptors, but were inactive at 5-HT2βApi receptors, and
ketanserin was active at 5-HT2βApi but not 5-HT2αApi receptors.
Although not widely tested, 5-nonyl-5-HT and DOI acted as agonists
at 5-HT2αMan receptors, whereas they displayed no activity at other
Manduca 5-HT receptors (Dacks et al., 2013). Röser et al. (2012)
found that methiothepin and methysergide were antagonists at 5-
HT2αCal receptors, but at 5-HT7Cal receptors the former was inactive
and the latter acted as an agonist. In P. interruptus, ritanserin, (+)-
butaclamol and cinanserin were antagonists at 5-HT2βPan
receptors, but inactive at 5-HT1αPan receptors; in P. clarkii,
methiothepin and cinanserin were antagonists at 5-HT2βPro
receptors, but inactive at 5-HT1αPro receptors (Spitzer et al., 2008).
In Lymnaea, mCPP and DOB acted as agonists at 5-HT2Lym
receptors, and a number of active antagonists were identified
(Gerhardt et al., 1996). As in 5-HT1Lym, several synthetic ligands
were more potent at 5-HT2Lym receptors than 5-HT itself. Detailed
pharmacology is not available for other molluscan 5-HT2 receptors,
but Nagakura et al. (2010) reported that pirenperone acted as
an antagonist in A. californica, whereas spiperone was inactive.
The nematode receptors 5-HT2(a)Cae and 5-HT2Asc displayed
Journal of Experimental Biology (2018) 221, jeb184838. doi:10.1242/jeb.184838
considerable overlap in their pharmacological profiles. Both
had high affinity for the agonist lisuride and the antagonists (+)-
butaclamol, methiothepin, cyproheptadine, clozapine and
metergoline, whereas both had relatively low affinity for
ketanserin, DOI and 8-OH-DPAT. The receptors differed in their
affinity for 5-HT, which was much higher for 5-HT2Asc relative to
5-HT2(a)Cae. This difference, also observed in nematode 5-HT1
receptors, might reflect the difference in size and life history
between C. elegans and the parasitic species, H. contortus and
Ascaris suum. The parasites are huge compared with C. elegans,
yet all of the worms have the same body structure and a surprisingly
similar neuronal wiring pattern. Possibly the high receptor affinity
for 5-HT facilitates signalling within the much larger worms
(Huang et al., 2002; Komuniecki et al., 2012).
The pharmacology of insect 5-HT7 receptors, currently described
in seven species, resembles that of other families in that 5-HT was
more potent than other synthetic agonists. Other agonists tested
across species included 5-CT, which acted with variable potency at
all receptors tested (5-HT7Aed, 5-HT7Api, 5-HT7Cal, 5-HT7Tri and 5-
HT7Pie), 5-MeOT (active in 5-HT7Cal, 5-HT7Tri and 5-HT7Pie) and 8-
OH-DPAT, which was a relatively poor agonist in most receptors
(5-HT7Api, 5-HT7Cal, 5-HT7Tri and 5-HT7Pie). Methiothepin was a
potent antagonist or inverse agonist where tested (5-HT7Api, 5-
HT7Tri, 5-HT7Pie), whereas other drugs, including the selective
mammalian 5-HT7 antagonist SB-269970, clozapine and
ketanserin, had variable effects across species. In C. vicina,
results highlight possible drug selectivity: the agonists R(+)-
lisuride and AS-19, and the antagonist spiperone were active at 5-
HT7Cal but not 5-HT2αCal receptors (Röser et al., 2012).
Data on 5-HT7 pharmacology are limited in molluscs and
nematodes. Lee et al. (2009) reported that, in the Aplysia receptor
5-HT7Aplku, methiothepin was by far the most potent antagonist,
followed by clozapine. Other antagonists were much less effective
or inactive. 5-HT7Cae resembled 5-HT1 and 5-HT2 receptors from
C. elegans in the high potency displayed by methiothepin and
clozapine, and the only agonist tested (tryptamine) was less potent
than 5-HT (Hobson et al., 2003). As noted above, 5-HT7 receptors
have been characterized in several species from the phylum
Platyhelminthes, and pharmacology has been investigated in the
human parasite Schistosoma mansoni. In 5-HT7aSch, the agonist o-
methyl-5-HT and 5-HT were similar in potency, and additional
agonists (buspirone, tryptamine and 8-OH-DPAT) were much less
potent than either o-methyl-5-HT or 5-HT, whereas cyproheptadine,
chlorpromazine and mianserin were active antagonists (Patocka
et al., 2014). In a further study, Chan et al. (2016c) screened a large
battery of compounds with the aim of comparing drug activity at
5-HT7aSch receptors with that at the human 5-HT7 receptor. Most
drugs displayed higher potency at the human receptor, but some
were more active at 5-HT7aSch (bromocriptine, rotundine,
tetrabenazine and tetrandrine), thus identifying these drugs as
potential targets for the development of new anthelmintics.
Receptors cloned from cestodes were activated by the non-
specific agonists egotamine and LSD, though the latter had
antagonist rather than agonist activity at 5-HT7bEch receptors. Two
cestode receptors, 5-HT7bEch and 5-HT7Mes, responded to 5-HT with
EC50 values in the picomolar range, indicating unusually high
sensitivity to the transmitter (Camicia et al., 2018).
Across receptors and species, MeOT and methiothepin emerged
as the most consistently effective agonist and antagonist,
respectively. Hence, should a research question call for engaging
multiple 5-HT receptors simultaneously, these two drugs could be
useful in many species. Certain well-established vertebrate agonists
N
7
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such as 8-OH-DPAT had low potency at most invertebrate receptors,
especially in insects. For some ligands, data are incomplete because
they have not yet been tested in more than a single receptor subtype.
To determine whether ligands possess selectivity, it would be useful
if those shown to be effective in one receptor subtype (e.g. PAPP in
molluscan and nematode 5-HT1 receptors) were systematically
tested in other subtypes. In a few cases, ligands tested on multiple
receptors within a species show promising selectivity, but thus far
these findings do not appear to extend to other species. Instead,
ligands that have been relatively widely tested show different effects
across receptor subtypes in different species, even within a single
phylum. Hence, at the present time, no selective ligands for
any invertebrate 5-HT receptor subtypes have been definitively
identified. In contrast to the variability of pharmacological profiles,
transduction mechanisms associated with 5-HT1, 5-HT2 and 5-HT7
receptors appear to be very well conserved across invertebrate phyla
and between invertebrates and mammals.
Linking heterologously expressed receptors to endogenous
receptors
Expression in heterologous systems can introduce significant
changes in receptor function, and hence it is important to confirm
that properties displayed in host cells are replicated in native tissue.
In model organisms, confirming the function of cloned receptors
can be addressed directly by techniques that isolate a receptor of
interest in native tissue. For example, following a feeding assay to
screen many drugs, Gasque et al. (2013) examined responses to
methiothepin in Drosophila 5-HT receptors expressed in HEK293
cells and also used null mutants of each receptor subtype to examine
responses to the drug in larvae. These experiments confirmed that
all five receptors, whether expressed or endogenous, were blocked
by methiothepin and identified 5-HT2αDro as the only receptor
mediating the effect of the drug on larvae feeding. In C. elegans, use
of null mutants has provided information on how receptor subtypes
contribute to feeding, locomotion and egg-laying behaviours
(Hobson et al., 2006; Hapiak et al., 2009). Furthermore,
C. elegans itself can be used as a heterologous expression system,
allowing receptors from parasitic worms to be pharmacologically
screened in nematode tissue, which mimics native tissue more
closely than do mammalian cells (Welz et al., 2011; Komuniecki
et al., 2012). Law et al. (2015) used this approach to examine
individual 5-HT receptor subtypes from H. contortus and other
species in C. elegans made null for all five endogenous 5-HT
receptors. In the flatworm Dugesia tigrina, Zamanian et al. (2012)
developed a loss-of-function technique that could be used to assess
the role of specific receptors in drug responses in native tissue. In
this approach, responses to drugs were compared in control tissue
and following RNAi knockdown (see Glossary) of a 5-HT7
receptor, allowing identification of drugs dependent on a single
receptor (Zamanian et al., 2012). These techniques in model
organisms have not yet been used in a comprehensive comparison of
heterologously expressed and in vivo receptors, but they offer
powerful options for future comparisons of pharmacology in each
situation.
Because 5-HT is so widely distributed and important in numerous
behavioural and physiological processes, determining the function
of 5-HT extends well beyond model organisms and strictly
molecular approaches. Many studies have used 5-HT and 5-HT
ligands to target receptors in vivo and draw conclusions about their
function in physiology (e.g. Smith and Walker, 1974; Tembe et al.,
1993; Ali and Orchard, 1994; Zhang and Harris-Warrick, 1994;
Leake and Koubanakis, 1995; Dumitriu et al., 2006; Inohara et al.,
Journal of Experimental Biology (2018) 221, jeb184838. doi:10.1242/jeb.184838
2015) and behaviour (e.g. Yeh et al., 1997: Tierney et al., 2004;
Johnson et al., 2009; Rawls et al., 2010). Receptor subtypes
identified in such studies often rely on drug application alone and
must be viewed as provisional given the lack of specificity shown by
available ligands and uncertainty about the site(s) where drugs acted
to produce observable effects. However, these studies are important
as they begin to address the question of receptor function in intact
tissues and organisms. Also, they provide a foundation for
molecular investigations by identifying tissues, receptors or drugs
relevant to serotonergic processes. For example, blowfly salivary
gland physiology has been investigated for five decades, and the
role of 5-HT in mediating increases in both Ca2+ and cAMP is well
documented (Berridge, 2005). This information pointed to the
likely presence of 5-HT2 and 5-HT7 receptors, and led to the
molecular characterization of 5-HT2αCal and 5-HT7Cal and a
valuable comparison between the cloned receptors and those in
native salivary gland membranes (Röser et al., 2012). Many
additional receptors have been cloned following intensive study of
5-HT function in diverse processes, including synaptic plasticity
(Barbas et al., 2002; Lee et al., 2009; Nagakura et al., 2010),
modulation of motor pattern generation (Clark et al., 2004; Spitzer
et al., 2008), reproduction (Ongvarrasopone et al., 2006; Tanabe
et al., 2010; Wang and He, 2014), regeneration (Saitoh et al., 1997;
Nishimura et al., 2009), movement (Patocka et al., 2014) and other
behaviours (Thamm et al., 2010, 2013; Gasque et al., 2013; Hobson
et al., 2006).
Data on molecular structure and function should in turn inform
current and future research with whole organisms. Indeed, a
compelling reason for describing the pharmacology of cloned
receptors is to use this information to more accurately manipulate
5-HT receptor subtypes in vivo. For some organisms, within-species
data on receptor subtype pharmacology are already available and
could shape physiological and behavioural investigations. However,
for most invertebrates, the discovery of drugs that act specifically at
5-HT receptor subtypes would be extremely useful. In the
meantime, screening large arrays of drugs in intact animals could
aid in identifying 5-HT ligands associated with specific phenomena.
Some species offer unique whole-animal assays for this purpose.
The free-living Platyhelminthe D. japonica displays an
extraordinary response to praziquantel in which regenerating
worms exposed to the drug invariably develop two heads, a
response mediated by 5-HT receptors (Nogi et al., 2009; Chan et al.,
2015). The bipolarity response was used to screen serotonergic
ligands, yielding ideas about structure–activity relationships at the
receptor binding site and contributing to the search for new
antihelmintics. More generally, mammalian researchers have long
conducted high-throughput screening of drugs using simple,
unambiguous behaviours, such as the time rodents struggle to
escape during tail suspension or forced swimming (Castagné et al.,
2011). Similar approaches are used in invertebrate model species
(Nichols et al., 2012; Blazie and Jin, 2018) and could be more
widely developed in non-model organisms. Efficient assays may
uncover novel invertebrate-specific ligands that can be assessed in
detail at the molecular level, and selected for investigations of
complex behaviours such as aggression, anxiety and mate choice.
In addition to pharmacology, many molecular investigations
yield information about the location of receptor subtypes. The
distribution of receptors, mapped using techniques such as
immunocytochemistry, in situ hybridization and RT-PCR, can
give clues about function that confirm past work and suggest ideas
for future focused experiments. 5-HT receptors are often found to be
CH3
abundant in the nervous system, as expected of a neurotransmitter
8
REVIEW
system important in behaviour. High expression of receptors in
particular brain regions or neurons has implicated specific receptor
subtypes in processes such as phototaxis (Thamm et al., 2010),
modulation of the stomatogastric nervous system (Clark et al., 2004;
Troppmann et al., 2010), activity of Aplysia bag cells (Barbas et al.,
2002), pharyngeal pumping (Hobson et al., 2003) and olfaction
(Dacks et al., 2013). Receptor subtypes have also been localized in
ovaries (Tanabe et al., 2010; Wang and He, 2014), Malpighian
tubules (Paluzzi et al., 2015) and hindgut (Pietrantonio et al., 2001),
consistent with their functional role in these organs.
Concluding remarks
Much remains to be determined about the role played by individual
receptor subtypes in these processes and organs. The 5-HT system,
with its ancient origins and evolution over eras of time, is very
complex. Despite decades of intensive research, the intricate
functioning of mammalian 5-HT receptors is only partly
understood, and numerous studies continue to explore the link
between 5-HT and human pathologies, especially depression, anxiety
and psychosis. The study of 5-HT in invertebrates is no less important
to human well-being. Insects, nematodes and flatworms inflict a
heavy disease burden on many human populations, and organisms
from the same phyla impose economic hardship through their
destruction of crops and livestock. Better understanding of 5-HT
receptors, especially their pharmacology, is key to the development of
more-precise, effective drugs and pesticides (Komuniecki et al.,
2012; Chan et al., 2015). A future challenge in this endeavour is to
determine how ligand responses are affected by differences in
species, receptor subtype and methodology. The study of 5-HT in
invertebrates also has much to contribute to our understanding of
receptor evolution and how transduction mechanisms and ligand
binding sites are conserved or diverge over time. This endeavour
would be aided by the development of a common nomenclature,
allowing relationships among receptors to be more easily recognized
in different species and phyla.
Acknowledgements
I thank James Wallace and Iona Mackillop for their comments on this review.
Competing interests
The author declares no competing or financial interests.
Supplementary information
Supplementary information available online at
http://jeb.biologists.org/lookup/doi/10.1242/jeb.184838.supplemental.
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