bk-2017-1265.ch007

Chapter 7

Molecular Pharmacology and Physiology of Insect Biogenic Amine Receptors Downloaded by UNIV OF FLORIDA on December 20, 2017 | http://pubs.acs.org Publication Date (Web): October 24, 2017 | doi: 10.1021/bk-2017-1265.ch007

Jia Huang* Institute of Insect Sciences, Zhejiang University, Hangzhou 310058, China *E-mail: [email protected].

Insect biogenic amines play important roles in mediating behavioral and physiological processes as neurotransmitters, neuromodulators and neurohormones. They activate specific G-protein coupled receptors on the cell surfaces to induce downstream signaling pathways. These biogenic amine receptors show different pharmacological properties from their vertebrate counterparts and therefore become potential targets for pest control. However, their physiological functions are not well understood. We summarize our recent progress on insect biogenic amine receptors, and emphasize the characterizations of novel receptors and their functions in behavior and immunity.

Introduction In vertebrates, biogenic amines such as dopamine, serotonin, epinephrine and norepinephrine act physiologically as neurotransmitters, neuromodulators and neurohormones to regulate many important processes. In contrast, norepinephrine and epinephrine do not appear to be present in insects, as insects lack dopamine β-hydroxylase that converts dopamine to norepinephrine. In fact, their role is fulfilled by their invertebrate counterparts, the monoamines tyramine and octopamine (Figure 1). The insect biogenic amines carry out many of the physiological roles such as reproduction, development, growth, circadian rhythms, endocrine secretion, and behaviors. They exert their effects by binding to specific receptor proteins that belong to the superfamily of G-protein coupled receptors (GPCRs), many of which have been characterized not only from the fruit fly Drosophila melanogaster but also from several other insect species. Thus, blocking or over stimulating these GPCRs in insect pests may either © 2017 American Chemical Society Gross et al.; Advances in Agrochemicals: Ion Channels and G Protein-Coupled Receptors (GPCRs) as Targets for Pest ... ACS Symposium Series; American Chemical Society: Washington, DC, 2017.

Downloaded by UNIV OF FLORIDA on December 20, 2017 | http://pubs.acs.org Publication Date (Web): October 24, 2017 | doi: 10.1021/bk-2017-1265.ch007

result in the death or reduce fitness to control pest populations. Therefore, insect biogenic amine receptors are potential targets for the development of next generation of insecticides. We used a combination of approaches from cell biology, molecular biology, neurobiology, immunology and genetics to study the pharmacology and physiology of biogenic amine receptors in lepidopteran pests and D. melanogaster. In the meantime, we also discovered several novel families of biogenic amine receptors.

Figure 1. Biosynthetic pathway of biogenic amines. (A) Biosynthetic pathway of dopamine, norepinephrine, tyramine and octopamine. DβH, dopamine β-hydroxylase; DDC, Dopa decarboxylase; TDC, tyrosine decarboxylase; TβH, tyramine β-hydroxylase; TH, tyrosine hydroxylase. (B) Serotonin biosynthetic pathway. Tryptophan hydroxylase (TRH/TPH), aromatic L-amino acid decarboxylase (AADC).

A Novel Octopamine Receptor Octopamine regulates many physiological processes in insects through specific octopamine receptors on the cell membranes. The first insect octopamine receptor gene oamb was isolated from the mushroom body of the fruit fly D. melanogaster (1). Subsequently, a variety of octopamine receptors were cloned from several other insect species. Based on the structural and signaling similarities between cloned D. melanogaster octopaminergic receptors and vertebrate adrenergic receptors. Evans and Maqueira (2) proposed a new classification system, which divided insect octopaminergic receptors into two classes: α-adrenergic-like receptors (OA1) and β-adrenergic-like receptors (OA2). Activation of OA1 receptors primarily leads to the elevation of [Ca2+]i 128 Gross et al.; Advances in Agrochemicals: Ion Channels and G Protein-Coupled Receptors (GPCRs) as Targets for Pest ... ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


when expressed in cell lines (3, 4). The OA2 receptors are divided into three subclasses, which all increase intracellular cAMP levels (5). Both OA1 and OA2 receptors show high specificity to octopamine over other biogenic amines such as tyramine and dopamine.

Figure 2. Agonists and antagonists of insect biogenic amine receptors (listed in the order that they appear in the text). 129 Gross et al.; Advances in Agrochemicals: Ion Channels and G Protein-Coupled Receptors (GPCRs) as Targets for Pest ... ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


We have cloned and functionally characterized an octopamine receptor from the rice stem borer, Chilo suppressalis, which is one of the most economically important rice pests in Asia, northern Africa, and southern Europe. Orthologous receptors have not been isolated from other invertebrate species. Structural and pharmacological studies demonstrated that this gene belongs to a novel family of octopamine receptors, which we named CsOA3 receptor (6). The CsOA3 encodes two polypeptides, CsOA3S and CsOA3L, that are generated by alternative splicing. CsOA3L differs from CsOA3S by the presence of an additional 30 amino acids within the third intracellular loop. Phylogenetic analysis clearly indicates that CsOA3 clusters with predicted orthologous genes of D. melanogaster and Tribolium castaneum in a distinct clade. A closely related clade contains the human α2-adrenergic receptors. When heterologously expressed, activation of CsOA3 by octopamine primarily leads to decrease forskolin-stimulated [cAMP]i. It can also be activated by tyramine, but with lower potency and efficacy. CsOA3 shows a distinct pharmacology to reported octopamine and tyramine receptors (7). Naphazoline and clonidine act as potent agonists (Figure 2). Phentolamine and epinastine are able to block CsOA3 while yohimbine, chlorpromazine and mianserin are not effective.

A Novel Serotonin Receptor Serotonin (5-hydroxytryptamine; 5-HT) is a small molecule found in organisms across the animal kingdom. It modulates a wide variety of processes in most vertebrates and invertebrates. Except the 5-HT3 receptor, a ligand-gated cation channel, vertebrate serotonin receptors have been classified into six main classes (5-HT1A/B/D/E/F, 5-HT2A/B/C, 5-HT4, 5-HT5A/B, 5-HT6, 5-HT7) and three of them are also found in insects (5-HT1A/B, 5-HT2A/B and 5-HT7). The 5-HT1 receptors couple preferentially to Gi/o proteins and inhibit cAMP production. The 5-HT2 receptors couple preferentially to Gq/11 proteins, which lead to an increase in [Ca2+]i. The 5-HT7 receptors couple preferentially to Gs proteins and induce cAMP production (8). We isolated a GPCR cDNA encoding a potential serotonin receptor from the caterpillar of the small white butterfly, Pieris rapae, which shares relatively low similarity to the known serotonin receptor families (9). After heterologous expression in HEK-293 cells, this new receptor can be activated by serotonin, but not other biogenic amines, in a concentration-dependent manner. We propose this receptor represents a new group of serotonin receptors, and designate it Pr5-HT8. Bioinformatic studies indicate that species orthologues of Pr5-HT8 are mainly found in lepidopteran and coleopteran pests such as the diamondback moth Plutella xylostella, the red flour beetle Tribolium castaneum and also in the genome of the malaria mosquito Anopheles gambiae. However, it is not found in the genome of honey bee Apis mellifera, parasitoid wasp Nasonia vitripennis or other mammals. The phylogenetic analysis also show that Pr5-HT8 receptor does not cluster with reported 5-HT receptors, but it clusters with the predicted insect 5-HT8 family in a distinct clade. Besides serotonin, classical serotoninergic agonists 5-methoxytryptamin, 8-OH-DPAT and 5-carboxamidotryptamine 130 Gross et al.; Advances in Agrochemicals: Ion Channels and G Protein-Coupled Receptors (GPCRs) as Targets for Pest ... ACS Symposium Series; American Chemical Society: Washington, DC, 2017.

(Figure 2) activate Pr5-HT8 to induce calcium response, suggesting that Pr5-HT8 selectively couples to Gq protein to activate phospholipase C, leading to a signaling cascade that ends with an elevation of [Ca2+]i. A surprising discovery is that methiothepin, a nonselective serotonin receptor antagonist, can also activate Pr5-HT8. However, SB 269970, SB 216641 and RS 127445 have no blocking effect except WAY 100635, a 5-HT1A antagonist, can inhibit serotonin-induced [Ca2+]i increases. Thus, the pharmacological profiles of Pr5-HT8 differ from that of other serotonin receptors.


Characterization of Three Dopamine Receptors Dopamine acts as an important neurotransmitter and neuromodulator to regulate a variety of physiological responses and behaviors in insects, such as learning and memory, cognition, sexual orientation, locomotion, phase change, etc. In vertebrates, five distinct dopamine receptors mediate all known functions of dopamine. They can be divided into two subfamilies based on their structural and pharmacological properties: D1-like receptors (D1 and D5), and D2-like receptors (D2, D3 and D4). Insect D1-like receptors also have two subtypes, DOP1 and DOP2, which elevate intracellular cAMP levels upon activation. However, DOP2 can also increases [Ca2+]i levels and is considered as a invertebrate-specific dopamine receptors which show similarities in structural, signaling and pharmacological properties with OA1 receptors. DOP3 are functionally D2-like and inhibit adenylyl cyclase (10). A Drosophila GPCR (DopEcR) that can be activated by both DA and ecdysteroids has been reported and it shares a high level of amino-acid sequence similarity with β-adrenergic receptors. We have pharmacologically characterized three types of dopamine receptors, CsDOP1, CsDOP2 and CsDOP3, from the rice striped stem borer, Chilo suppressalis (10). They all show considerable sequence similarity with orthologous dopamine receptors and phylogenetic analysis also clusters the receptors within their each group. Transcript levels of CsDOP1, CsDOP2 and CsDOP3 are all significantly high in the central nervous system, indicating their important roles in neural processes. After heterologous expression in HEK 293 cells, CsDOP1, CsDOP2 and CsDOP3 are dose-dependently activated by dopamine and synthetic dopaminergic agonists (Figure 2). The rank orders of agonist activity for CsDOP1 is dopamine > bromocriptine > 6,7-ADTN > pramipexole. For CsDOP2, only dopamine and 6,7-ADTN can activate the receptor significantly and bromocriptine also shows high agonist activity on CsDOP3. The rank order of potency of tested antagonists on CsDOP1 is the following: butaclamol ≥ SCH-23390 > chlorpromazine ≥ flupenthixol > mianserin > phentolamine ≥ spiperone > yohimbine > propranolol ≥ ketanserin. The rank order for CsDOP2 is: chlorpromazine ≥ clozapine ≥ SCH-23390 ≥ epinastine ≥ mianserin ≥ flupenthixol ≥ butaclamol > phentolamine > prazosin > spiperone ≥ sulpiride. For CsDOP3, the rank order of potency of antagonists is the following: epinastine > mianserin > SCH-23390 > chlorpromazine. 131 Gross et al.; Advances in Agrochemicals: Ion Channels and G Protein-Coupled Receptors (GPCRs) as Targets for Pest ... ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


Tyramine Receptor Modulates Courtship Behavior In insects, tyramine is a decarboxylated product of tyrosine and further hydroxylated to produce octopamine. For a long time, it was assumed to serve as a biosynthetic precursor of octopamine, rather than as a neuroactive substance. Therefore, not much is known about the physiological role of tyramine. In the last decade, increasing reports have supported the hypothesis that tyramine is not only a precursor but also a potential genuine signaling molecule in a variety of physiological processes. However, it is still unclear whether tyramine acts as an independent neuromodulator in vivo due to the lack of solid genetic evidences. Although there is one point-mutation allele for Drosophila Tdc2 (Tdc2RO54), which is the major tyrosine decarboxylase in central nervous system. Thus, the Tdc2RO54 allele abolishes most tyramine and octopamine; and the Tβh null allele Tβhnm18 allele has no octopamine but 10 times higher of tyramine compared to control (11). Considering even simple behaviors may include complex neuro-circuits with multiply neurotransmitters and neuromodulators involved, it is impossible to make clear conclusions about the role of tyramine with above two alleles. Three tyramine receptors were identified in Drosophila: Oct-TyrR (CG7485), TyrR (CG7431) and TyrR2 (CG16766). Oct-TyrR couples to Gi and Gq proteins when heterologously expressed in cell lines and shows a pharmacology profile with slightly higher potency to tyramine over octopamine and dopamine (12, 13). TyrR2 is also like Oct-TyrR to coupled to Gi and Gq proteins but have a higher preference for tyramine than other amine (14). However, TyrR is an unusual insect biogenic amine receptor since it shows a very high specificity for tyramine (EC50 = 3 x 10-7 M). Structurally related biogenic amines, such as octopamine, synephrine and dopamine did not show any effects up to a concentration of 100 μM on TyrR (15) or on its species homologue from the silkworm, Bombyx mori (16). Nevertheless, of all the octopamine and tyramine GPCRs, TyrR is the only one to show activity to tyramine but not other biogenic amines. Therefore, we reasoned that we can disclose the physiological role of tyramine through generation of a TyrR knock-out allele in that any defect of TyrR mutant can only be attribute to its solo endogenous ligand, tyramine (17). To simultaneously generate mutations and gene reporters, we used ends-out homologous recombination to insert the GAL4 gene at the site of the normal TyrR translation initiation codon. At the same time, we deleted a ~0.7 kb exon including the N-terminal coding region and the first two transmembrane domains of TyrR. These TyrRGal4 males show strong male-male courtship behaviors (Figure 3). When 8-10 TyrRGal4 males are introduced into a small Petri dish together, they serially chase each other to exhibit a chain formation in which males court each other and produce courtship song. Either knocking down TyrR expression by RNAi or activation of TyrR neurons also phenocopied the chaining behavior. These results demonstrate that tyramine might act as an inhibitory neuromodulator in vivo, which is consistent with previous in vitro physiological studies showing that tyramine reduces the amplitude of excitatory junction potential (EJP) in neuromuscular junctions. Genetic and behavioral studies further indicates that TyrR activity is required in a small group of neurons in the brain, which may form 132 Gross et al.; Advances in Agrochemicals: Ion Channels and G Protein-Coupled Receptors (GPCRs) as Targets for Pest ... ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


synaptic connections with the male-specific Fruitless protein (FruM) neurons to regulate courtship (17).

Figure 3. TyrR Gal4 mutant showed enhanced courtship behavior. (A) The expression pattern of the TyrR reporter (TyrRGal4/+) in the brain. The red arrows indicate the location of some of the neurons expressing the TyrR reporter. SMP, superior medial protocerebrum; PLP, posteriorlateral protocerebrum; IPS, inferior posterior slope; GNG, gnathal ganglia. MB, mushroom body; AL, antennal lobe; OL, optical lobe. (B) Model illustrating the proposed role of TyrR and IPS neurons in the male fly brain in the regulation of courtship behaviors. Tyramine and octopamine are released from Tdc2 neurons in response to a close encounter with a male. Octopamine promotes male aggression. The tyramine activates the TyrR, which in turn inhibits TyrR-expressing IPS (TyrRIPS) neurons. In the absence of inhibition, the TyrRIPS neurons release acetylcholine, which promotes courtship. (Reproduced with permission from reference (17) Copyright 2016 Elsevier.).

Serotonin Receptors Regulate Immunity The immune system needs to be tightly regulated and highly responsive to changes in external and internal environments. Neurohormones affect the function of the immune system, but how they do so is not well understood. Serotonin modulates both neural and immune responses in mammals, where various types of immune cells that engulf foreign particles or microorganisms through a process called phagocytosis, have receptors for serotonin on their cell surface and are 133 Gross et al.; Advances in Agrochemicals: Ion Channels and G Protein-Coupled Receptors (GPCRs) as Targets for Pest ... ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


activated when serotonin is present. Serotonin is also known to influence many processes in insects, such as appetite, sleep and reproduction, but its role in insect immunity is still unclear. Besides, it is also elusive how the immune response is regulated and coordinated by neurohormones at the level of the whole organism.

Figure 4. A schematic diagram of serotonin signaling on hemocyte phagocytosis. Lipopolysaccharide (LPS) enhances the expression of tryptophan hydroxylase (TPH), which catalyzes tryptophan into serotonin via 5-hydroxy tryptophan (5-HTP). Serotonin, which is secreted from hemocytes, activates the hemocyte-membrane receptor 5-HT1B and 5-HT2B. The immune responses of P. rapae are labeled in purple: activation of 5-HT1B promotes hemocyte phagocytosis and activation of 5-HT2B lead to opposite effects. LPS increases 5-HT1B expression but decreases that of 5-HT2B. The immune responses of Drosophila are labeled in green arrows: activation of 5-HT1B promotes hemocyte phagocytosis and activation of 5-HT2B leads to the same effects. (Reproduced from reference (18). Permission is not required from eLife). We found that hemocytes (insect blood cells) in the caterpillar, Pieris rapae are able to synthesize and release serotonin following activation by lipopolysaccharide (LPS), the major component of the outer membrane of Gram-negative bacteria. The inhibition of a serotonin-generating enzyme with either pharmacological blockade or siRNA silencing results in significantly decreased hemocyte phagocytosis. Two distinct serotonin receptors (5-HT1B and 5-HT2B) are expressed on the cell surfaces of naive hemocytes. Using selective antagonists and RNAi, we found that inhibition of 5-HT1B decreases hemocyte phagocytosis. However, inhibition of 5-HT2B enhances hemocyte phagocytosis. Interestingly, 5-HT1B is dramatically up-regulated following hemocyte activation, but 5-HT2B is significantly down-regulated (Figure 4). We confirmed the role of 5-HT receptors in vivo using the D. melanogaster. D. melanogaster 5-HT1B 134 Gross et al.; Advances in Agrochemicals: Ion Channels and G Protein-Coupled Receptors (GPCRs) as Targets for Pest ... ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


deficient flies were more vulnerable to bacterial infections due to their poor phagocytosis ability, indicating that the 5-HT1B-mediated hemocyte phagocytosis is critical in the insect immune response to invading organisms. Flies expressing 5-HT1B or 5-HT2B RNAi in hemocytes also showed similar sensitivity to infection. This is the first molecular demonstration of serotonin receptors in an insect immune cell. This result establishes, at the molecular level, that animals from a phylum outside of the vertebrates could also use serotonin and its receptors to connect the nerve system to immune function. To our knowledge, it is also the first genetic evidence to show that loss of a neurohormone receptor leads to immunodeficiency. Further studies are needed to examine how physiological changes such as behaviors, nutritional state, and stress will affect insect immunity through serotonin signaling pathways (18).

Biogenic Amine Receptors as Pest Control Targets Many insecticidal chemicals can act on insect biogenic amine receptors (Figure 5). The octopamine receptor gets more attention since it is a bona fide target of a class of commercial insecticides, the formamidines. In 1980, Hollingworth (19) and Evans (20) first reported that the formamidine acaricide/insecticide, chlordimeform (CDM) and its N-demethylated derivative (DMCDM) acted as octopamine receptor agonists by physiological studies using insect native organs or tissues. We confirmed that DMCDM can activate the Bombyx mori α-adrenergic-like octopamine receptor (BmOAR1) to induce both cAMP and Ca2+ responses when expressed in HEK-293 cell lines (21). We further found that CDM and another formamidine insecticide, amitraz can also directly activate the Chilo suppressalis β-adrenergic-like octopamine receptor (CsOA2B2) and the above novel octopamine receptor CsOA3 (unpublished data). Recently, Kita et al. reported that amitraz and its metabolite N2-(2,4-dimethylphenyl)-N1-methyformamidine (DPMF) potently activate Bombyx mori α- and β-adrenergic-like octopamine receptors but their potencies on these two receptors are quite different (22). Besides, insecticidal essential oils are also believed to act on octopamine receptors (23). Enan found that α-adrenergic-like octopamine receptors from D. melanogaster and Periplaneta americana respond to cinnamic alcohol, eugenol and trans-anethole (24). However, we found that only eugenol at 100 μM, but not cinnamic alcohol and trans-anethole, can activate BmOAR1 to induce Ca2+ response (21). Tyramine receptors can also be activated by CDM (7) and plant essential oils (25, 26). For dopamine receptors, a yellow fever mosquito (Aedes aegypti) dopamine receptor (AaDOP1) was used in a chemical library screen, amitriptyline and doxepin were identified as antagonists and showed high toxicity in subsequent A. aegypti larval bioassays (27). There are few papers about insecticidal compounds that target serotonin receptors. However, one study used the 5-HT1A agonist PAPP (1-[(4-aminophenyl)ethyl]-4-[3-(trifluoromethyl)phenyl]piperazine) as a lead compound for new insecticides design and they found that most synthesized PAPP derivatives displayed certain growth-inhibiting activities or larvicidal activities against the armyworm, Pseudaletia separate (28). 135 Gross et al.; Advances in Agrochemicals: Ion Channels and G Protein-Coupled Receptors (GPCRs) as Targets for Pest ... ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


Figure 5. Insecticidal chemicals targeting insect biogenic amine receptors (listed in the order that they appear in the text).

Conclusion Insect biogenic amine receptors have unique pharmacological profiles, which are different from their counterparts in mammals. Some of them, like 5-HT8 receptor, are even restricted in few insect species (9). They are also involved in regulating a series of behaviors and key physiological functions. While octopamine receptors are an established insecticide target, there is no commercial insecticide targeting other biogenic amine receptors. Thus, insect biogenic amine receptors merit more studies which will promote the development of novel insecticides with novel mode of actions.

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