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Chapter 8
G-Protein-Coupled Receptors: Their Expression, Function and Regulation in Insecticide Resistance Ting Li and Nannan Liu* Department of Entomology and Plant Pathology, 301 Funchess Hall, Auburn University, Auburn, Alabama 36849, United States *E-mail:
[email protected] G-protein-coupled receptors (GPCRs) are known to play central roles in the physiology of various organisms. This seven α-helical transmembrane protein family is triggered by extracellular signals, actives its downstream effectors, and governs the intracellular and cell biological responses. Beyond the concepts of GPCR-physiological functions in insects, the implication of GPCRs in insecticide resistance development is less understood. Recent studies have revealed the expression and function of GPCRs in insecticide resistance, improving the understanding of the molecular complex governing the development of resistance. This article reviews current knowledge on the expression and function of GPCRs and their downstream-regulation pathways in insecticide resistance and their regulation on resistance P450 gene expression. It also discusses the new insights of these findings on the basic and practical aspects of resistance research.
Introduction The proteins sharing a seven α-helical transmembrane structure are named G-protein-coupled receptors (GPCRs) that govern several physiological processes in vertebrates and invertebrates. The main function of GPCRs is to transduce the extracellular signals and to regulate intracellular second messengers through © 2018 American Chemical Society
coupling to heterotrimeric G-proteins. Because of the critical function of GPCRs in cell physiology and biochemistry they play important roles in the development of clinic medicines for therapeutic a range of human diseases (1, 2). Several studies have revealed hundred GPCR genes and their potential biological functions that may impact the insect development, reproduction, metabolism, and ability to transmit diseases (3, 4). Insecticides worked as a primary component to control pests for the protection of crops and public health. However, insects developed resistance impairs pest eradication (5). Currently, GPCRs have been studied as new targets for the development of novel insecticides (5, 6). In addition to that, several GPCR genes have been identified to be up-regulated in insecticide resistant strains of mosquitoes (7–11) and house flies (8). The function of up-regulated GPCRs and their downstream intracellular cascades was investigated in insecticide resistance of Culex quinquefasciatus (9–11). Understanding the molecular basis of GPCRs in insecticide resistance could be fundamental to develop new strategies for pest control and resistance management in the future.
Insect Whole Genome Sequencing and GPCR Genes More than 800 human GPCR genes have been identified since 2003 (12), and approximate 500 mouse GPCRs showed high similarity of the orthologue pairs revealing a gene repertoire of GPCRs in mammalian organisms (13). In current decade, whole genome sequencing of various insect species revealed hundred GPCRs distribute in different organs and may play diverse roles in insects. Based on the genome sequencing study of the tobacco hornworm moth, 22 biogenic amine GPCRs and 52 neuropeptide and protein hormone GPCRs were characterized implicating specific functions of these GPCRs in neuropeptide signaling pathways in moths (14). The green bottle fly as one of important parasitic insects its genome sequencing reveals 197 GPCR, which were hypothesized to be involved in chemoreception and insecticide resistance development (15). The pyrosequence for forelegs of the cattle tick was analyzed and annotated 46 GPCR candidates belong to 3 classes of GPCR family releasing new information for pest control in the future (16). In Anopheles gambiae genome, a total of 276 GPCRs was sequenced and analyzed hypothesizing the potential involvement of GPCRs in mosquito’s life cycle (17). Whole genome sequence of Aedes aegypti revealed 111 nonsensory GPCRs present high similarity to known drug targets and provided new information for the development of novel insecticides (18). The red flour beetle is a model organism for studies on insect development and evolution and an important agriculture pest, of which the immune system was challenged by lipopolysaccharide and identified potential implication of abundant genes in the induced immune responses including several GPCR genes (19). The insect digestive system interfaces the insect and dietary habits, containing several metabolism enzymes including P450s and hydrolases. The transcriptome analysis of digestive system in plant bug identified four GPCR genes were identified including neuropeptide Y receptor, CAPA receptor and neuropeptide 154
155, indicating a potential regulation function of GPCRs in energy balance, lipid metabolism, and in detoxification of compounds (20). cDNA microarray by screening 1500 cDNA clones from an insecticide resistant-susceptible mosquito subtractive library identified a Rhodopsin-like GPCR gene was overexpressed in resistant strain of Culex quinquefasciatus indicating the involvement of GPCRs in insecticide resistance (7). Of 115 characterized GPCR and GPCR-related gene expression in whole transcriptome of five Culex mosquito strains, 4 GPCR genes were co-overexpressed with resistance-related P450 genes in highly resistant mosquito strains by comparison with filed resistance and lab susceptible strains (9, 10). The similar finding of functionally GPCRs in resistance is present in the house fly, Musca domestica, which is a major domestic, medical and veterinary pest that transmits over 100 human and animal intestinal diseases. The study of whole transcriptome of M. domestica analysis for the multiple insecticide resistance strains revealed GPCRs and their downstream effectors were co-overexpressed with metabolic detoxification cytochrome P450 genes in resistant fly strains (8). Li et al. (10) identified three annotated GPCR genes involved in insecticide resistance in Cx. quinquefasciatus, classifying into different subfamilies as CPIJ020021—long wavelength sensitive opsin (CqGPROP13), CPIJ014419—calcitonin receptor (CqCALCR1), and CPIJ019111—pteropsin (CqPter). A phylogenetic tree is constructed to compare the amino acid sequence of these GPCRs with other GPCRs in same annotation from human, house mouse, and two mosquito species (Aedes aegypti, Anopheles gambiae) (Figure 1). By the sequence alignment and phylogenetic tree, CqGPROP13 shared high similarity with CqGPROP10 and other two opsin genes (AaGPROP5 and AaGPROP4) from Ae. Aegypti; CqPter shared high similarity with AgGPROP12, AgGPROP1 from An. gambiae and AaGPROP12 from Ae. aegypti; CqCALCR1 shared high similarity only with AgGPRCAL1 from An. gambiae. In contrast, these three genes shared low similarity with genes from human and house mouse implying they could be developed as targets for new insecticides for mosquito control and insecticide resistance management (Figure 1).
GPCR and GPCR-Regulation Pathways The GPCR regulation pathways are crucial in cell signaling transduction that regulate several cell functions (e.g., cell proliferation, survival, differentiation, migration, extracellular matrix degradation, angiogenesis, metastasis, cancer, etc) (21). GPCR downstream effectors in many signaling pathways have been identified to be targets for the development of new medicines for disease prevention and treatment. For example, in the phosphoinositide 3-kinase pathway, various inhibitors targeting downstream effectors, such as receptor tyrosine kinases, AKT, and mTOR, have entered the clinical trial (22); as well as the Hippo pathway present in both mammals and Drosophila involved in cell proliferation, death, and differentiation through regulating gene transcription (23). 155
Figure 1. The phylogenetic tree includes 12 Culex quinquefasciatus(Cq) GPCRs, 7 Aedes aegypti(Aa) GPCRs, 11 Anopheles gambiae(Ag) GPCRs, 9 Homo sapiens(Hs) GPCRs and 7 Mus musculus(Mm) GPCRs. All of the GPCR genes in same annotation were searched from published genome sequences from different species. Sequence alignment was conducted in MEGA7 and phylogenetic tree was constructed using neighbor-joining method by MEGA7 with 1000 bootstrap replicates. The gene ID numbers for sequences utilized in phylogenetic analysis in Figure 1: CqGPROP13 (CPIJ020021), CqGPROP6 (CPIJ011571), CqGPROP9 (CPIJ011576), CqGPROP5 (CPIJ012052), CqGPROP7 (CPIJ011573), CqGPROP10 (CPIJ013056), CqGPROP1 (CPIJ004067), CqGPROP8 (CPIJ011574), CqCALCR1 (CPIJ014419), CqCALCR2 (CPIJ009749), CqCALCR3 (CPIJ011559), CqPter (CPIJ014334); AaGPROP1 (AAEL006498), AaGPROP2 (AAEL006259), AaGPROP3 (AAEL006484), AaGPROP5 (AAEL005625), AaGPROP4 (AAEL005621), AaGPROP7 (AAEL007389), AaGPROP12 (AAEL005373); AgGPROP7 (AGAP002462), AgGPROP3 (AGAP012982), AgGPROP1 (AGAP013149), AgGPROP4 (AGAP012985), AgGPROP5 (AGAP001162), AgGPROP6 (AGAP001161), AgGPRCAL3 (AGAP003654), AgGPRCAL2 (AGAP001175), AgGPRCAL1 (AGAP009770), AgGPROP12 (AGAP002444), AgGPROP11 (AGAP002443); HsOPN1LW (OPN1LW-202), 156
HsOPN1LW-201 (OPN1LW-201), HsCALCR-204 (CALCR-204), HsCALCR-206 (CALCR-206), HsCALCR-205 (CALCR-205), HsCALCR-202 (CALCR-202), HsCALCR-207 (CALCR-207), HsCALCR-201 (CALCR-201), HsCALCR-203 (CALCR-203); MmRho-201 (ENSMUSP00000032471), MmRho (NP_663358.1), MmRho-205 (ENSMUSP00000144952), MmRho-207 (ENSMUSP00000144768), MmCALCR1a (NP_001036190.1), MmCALCR2 (NP_062317.1), MmCALCR3 (NP_062384.1).
A Moody-mediated signaling pathway was identified to regulate behavioral responses of Drosophila to cocaine and nicotine stimulation, postulating a novel pathway involved in the function changes of blood-brain barrier responding to psychostimulants (24). Several GPCRs were triggered by neuropeptides and subsequently lead intracellular pathways that implicated in many physiological processes in insect species. For example, the adipokinetic hormone could bind with neuropeptide GPCRs to active different G-protein subunits that regulate diverse signaling pathways including activation of triacylglycerol lipase, DAG production, activation of glycogen phosporylase, etc. (25). The A-type allatostatin neuropeptides and receptors recently discovered in juvenile hormone biosynthesis in many insect species, such as in drosophila, cockroaches, crickets, and termites (25). An orphan neuropeptide receptor was identified in the silkworm showing overexpression of this GPCR in the corpora cardiaca and involved in the regulation of JH biosynthesis in the corpora allata (26). Calcitonin-like diuretic hormone play crucial role in insect secretion of Malpighian tubules via a Ca2+-dependent mechanism and cAMP driven in GPCR regulation pathways (27, 28). In the study of Malpighian tubules of the Asian tiger mosquito, abundant GPCRs showed differential expression in blood feeding and non-blood feeding mosquitoes, in which the GPCRs were considered to be involved in regulating multiple physiological pathways in mosquito Malpighian tubules (29). Interestingly, one insecticide resistance-related GPCR gene was identified to overexpress in Malpighian tubules of Culex mosquitoes by comparison with other tissues (10), indicating a possibility of GPCRs in insecticide resistance through post-prandial diuresis. Currently, a GPCR regulation pathway was investigated to be involved in insecticide resistance via downstream intracellular effectors including G-protein alpha s subunit, adenylyl cyclase, protein kinase A, to regulate resistance-related cytochrome P450 gene expression (9, 11) (Figure 2), which could metabolize insecticides in Culex mosquitoes (30). These studies revealed detailed information about how GPCR regulation pathway works in resistance development and opened a new window for pest management in the future. 157
Figure 2. A hypothetical model of G-protein-coupled receptor (GPCR) intracellular cascade in the insecticide resistance of insects. This model is developed according to the hypothetical pathway constructed for GPCRs in human cells (21) the discoveries in Liu’s research team (9–11). The constitutive expressed GPCR in resistant mosquitoes initially activate G-protein alpha s-subunit (Gαs) that subsequently stimulate adenylate cyclase to convert ATP to cAMP. cAMP is a crucial second messenger in intracellular regulation pathway and could activate protein kinase A, which may involve in the increased expression of cytochrome P450 genes and eventually cause elevation of detoxification ability of insects to insecticides. Inhibitions of cAMP production or PKA activity is able to interrupt this regulation pathway showing decreased production of cAMP or PKA activity is strongly associated with decreased expression of resistance-related P450 genes and increased sensitivity to insecticides in both mosquitoes and insect cell lines.
GPCRs and Insecticide Resistance Insecticide is a robust and predominant strategy to control pests to date. However, insect have developed resistance to insecticides causing pest control problems in both human health and agriculture. Researchers worldwide have identified two main mechanisms underlying insecticide resistance in many insect species, including increased metabolic detoxification of insecticides by enzymes and decreased sensitivity of the target site on which an insecticide act. Cytochrome P450 is a primary detoxification enzyme which could metabolize insecticides by mainly elevating gene/protein expression level (31, 32). The regulatory factors involved in the overexpression of P450 gene have been identified on autosomes 1 and 2 of house fly (33). Several transposons were detected in the introns, exons or flanking regions of six P450 genes which were associated with xenobiotic metabolism in corn earworm and drosophila (34). Transcriptional element 158
regulated xenobiotic induction of P450 genes has been functionally characterized in several insect species. These include EcRE/ARE/XRE-xan elements of Cyp6b promoters in tiger swallowtail (35) and black swallowtail (36) butterflies, the EcRE element of Cyp6b in black swallowtail butterflies (37), the CuRE element of Cyp9m10 in mosquitoes (38), and the XRE-Fla element of Cyp321a1 in corn earworms (39), and the CncC element of Cyp6a has been shown to be involved in phenobarbital (PB) induction in Drosophila melanogaster (40). Bhaskara et al. (41) reported that the caffeine-inducible promotion of Cyp6a genes was probably regulated through the cAMP pathway in D. melanogaster. In addition, Cnc and its heterodimer partner Maf was determined to be involved in the detoxification the expression of multiple P450 genes via binding with antioxidant-response elements (ARE) in red flour beetle and Colorado potato beetle (42, 43). The Cnc ortholog Nrf2 which is regulated by Keap1responsible for the oxidative stress or electrophilic xenobiotics. Nrf2/Cnc pathway in D. melanogaster has been identified in response to insecticide resistance (40). However, it has yet been clearly elucidated the intracellular regulation pathway involved in overexpression of cytochrome P450 genes in resistant insects (5). A co-overexpression of GPCR gene and P450 genes were detected in insecticide resistance mosquitoes since 2007 provided a new insight in the regulatory pathway of P450 gene expression in insecticide resistance (7).
Constitutively Active GPCR and GPCR Overexpression The constitutive (agonist-independent) activity/constitutive expression of GPCRs plays crucial roles in cell signaling regulation pathways (44) and provides valuable opportunities for receptor pharmacology research (45, 46). Active GPCRs transduce signals to G proteins that activate or inhibit intracellular factors (e. g., adenylyl cyclase, phospholipase, or ion channels) to elicit a cellular biological response (47). Constitutive expression of GPCRs present in diverse species and related to human diseases and therapeutic method development (44, 48). Arvanitakis et al. (48) found one constitutively active GPCR gene in genome of human herpesvirus and involved in protein kinase C cascade and cell proliferation. Mustafá et al. (49) identified a constitutively active GPCR involved in modulation of voltage-gated calcium channel expression that responsible for food take and memory in brain. Many constitutive activation of GPCRs were reported in midbrain dopamine regulation pathways which implicated in mood regulation, addictive behavior, food intake, obesity and negative emotions, etc. (50). Qin et al. (51) investigated an orphan GPCR was overexpressed in melanoma metastases and provided novel anticancer target for metastatic melanoma therapy. Constitutively expression GPCRs were also found to play diverse physiological functions in insect species. Two leucine-rich repeats containing GPCRs (LGRs) were identified in D. melanogaster. These two LGRs (dLGR3 and dLGR4) were overexpressed in different location and gender of flies indicating their potential roles in development and reproduction. dLGR3 was constitutive active caused increased production of cAMP in mammal cells (52). Constitutive 159
expression of diapause hormone GPCR receptors (DH-R) was present after putation stage of silkworm suggesting a critical function in insect diapause (53). In yellow fever mosquitoes, high level expression of DH-Rs in all developmental stages, especially in post-emergence days indicated the importance of HD-R in mosquito development (54). A sex peptide GPCR receptor was overexpressed in the prothoracic gland of silkworm corresponding to prothoracicostatic peptides synthesis at high level, investigating the function of this sex peptide receptor as a prothoracicostatic peptide receptor in silkworm and involved in the regulation pathway of ecdysteroidogenesis (55). An orphan GPCR gene was found in D. melanogaster and its function as a receptor for plant insecticide L-canavanine to help fly avoid taking toxin (56). A partial rhodopsin-like GPCR gene was first identified in insecticide resistance via cDNA microarray showing overexpression of this GPCR gene in resistant southern house mosquito (7); subsequently 4 GPCR and GPCR-related genes were found to overexpress in insecticide resistant mosquitoes and following insecticide selection suggesting the importance of these GPCR genes in insecticide resistance development (9, 10). In house fly, five GPCR genes were overexpressed in insecticide resistant flies and mainly located on autosome 2 where is predominant loci for regulatory factors (8). In the comparative transcriptome study of insecticide resistance strains of malaria mosquitoes, GPCRs in signaling transduction system were predicted in resistance via dynamic changes of gene expression (57). In honey bee, differential expression of GPCR genes were suggested that may play specific role in the regulation pathway of insecticide tolerance (58). These studies indicated the important function of GPCRs in insect physiological functions through constitutive expression.
GPCR Mutation(s) Caused Resistance The mutations of genes could cause conformational changes of proteins that may become toxic for the cell and/or are recognized as improper proteins for the interfere with signaling pathways. The single nucleotide polymorphisms (SNPs) of genes caused functional changes of GPCRs are associated with more than 30 different human diseases (59), and downstream effectors were identified to be regulated by the disease-causing mutations (60). As an example, in endocrine diseases some mutations of GPCRs cause the receptor loss-function to hormone action (61, 62), whereas some mutations of GPCRs result in constitutive activation of receptors as mimic hormone excess (63). Several significant mutations were identified across human cancer genomes (64), and some specific mutations were detected within high frequency of cancer populations (65), suggesting potential therapeutic targets for anti-cancer medicine development. In addition, the mutations of target GPCRs have caused the molecular target insensitivity and influence the function of downstream effectors, eventually resulting in drug resistance problems in therapeutic treatments for human diseases (66). The mutations of GPCRs were also widely identified in insect species. One of mutated GPCRs showed decreased binding affinity to plant insecticide L-Canavanine in D. melanogaster detecting an orphan GPCR receptor to 160
insecticide (56). Some mutated GPCRs were identified in a Drosophila mutant line, which showed resistance to various stress situations (67). But the function of these mutated GPCRs has yet been studied. One mutation in the pigment-dispersing factor receptor gene, named han, was investigated that involved in the regulation pathway of circadian behavioral rthythm in Drosophila (68). The hypomorphic mutations were detected in moody locus of Drosophila in which two novel GPCRs were encoded, and caused an increased sensitivity to cocaine and nicotine and associated to drug-related behavior (24). In addition, the mutations present on GPCRs could be utilized to pin point the functional region for ligands binding (69). By sequence comparison of metabotropic glutamate receptors among different insect species, the mutated region was mainly present on the residues interacting with the γ-carboxylic group causing a diverse recognition to different amino acid of glutamate, which may influence the response to glutamate in different insects (70). Functional study on multiple mutations in pheromone biosynthesis-activating neuropeptide (PBAN) investigated the specific function of each mutations and mutation combinations in the regulation of Ca2+ mobilization and the mutation locations in insect cell (71). Mutations caused acaricides-insensitivity occurred in octopamine/tyramine GPCRs of by showing several non-synonymous and synonymous mutations present in amitaz resistance ticks (72). But the function of these mutations in insecticide resistance need to be further studied.
GPCR Regulation Pathway Implicated in Resistance Cytochrome P450s are primary metabolic detoxification enzymes via elevated P450 levels present in insecticide resistant insects. Most regulatory factors involved in P450 gene expression has been identified as trans and/or cis-acting factors (73, 74). One of P450 genes, named CYP6A1, was overexpressed in insecticide resistance house fly and its regulatory factors were located on different chromosome suggesting a trans-acting factor involved in the regulation of resistance-related P450 gene expression (75). In a pyrethroid resistant house fly strain, a trans-acting factor has been mapped on loci of autosome II and involved in regulation of both inducible and overexpressed CYP6D1 gene (76). Moreover, co-overexpressed P450 gene, cytochrome b5, and P450 reductase were found in an insecticide resistance house fly strain, and their regulatory factors were determined on autosome 1 and 2 indicating a trans and/or cis regulation mechanism in P450 gene expression (77). However, the specific regulatory genes which is involved in the regulation of metabolic enzyme expression are still unclear. Recently, GPCRs and their downstream effectors were identified to be implicated in the regulation of detoxification gene expression in insects (8–11). This study is the first time to draw GPCRs and GPCR intracellular cascades into the concept of insecticide resistance of insects. The co-overexpression of GPCRs and P450 genes were identified in insecticide resistant house flies (8) and mosquitoes (7–11). The effectors in GPCR-led intracellular pathway has been investigated, showing GPCR, G-protein, adenylate cyclase, and protein kinase A worked as co-effectors in the 161
regulation of resistance-related P450 gene expression (9, 11). By allele-specific RT-PCR autosomal mapping study in house fly, one GPCR gene was mapped on autosome II and two intracellular effectors, protein kinase and adenylate cyclase, were mapped on autosome V and II, respectively. Interestingly, two P450 genes were located on autosome V of house fly hypothesizing GPCR and adenylate cyclase may be trans regulation genes and protein kinase may be cis regulation gene to regulate P450 gene expression in resistant insects (8). In addition, the structure of insect sodium channel was discussed that may have hypothetical interaction with cellular proteins, such as G-proteins and kinases (78), which could be another interesting story in insecticide resistance mechanism. Although GPCR and the intracellular cascade have been identified in gene interaction and regulation in insecticide resistance, it is still questioned how many intracellular cascades are involved and which regulatory factors are conserved or specific to metabolic detoxification genes in resistance regulation mechanism.
Functional Study of GPCR and GPCR Pathways Since the crucial function of GPCRs in insect physiology, the diverse functions of GPCRs have been investigated in insect species. Because neuron peptides are present in insect brain and play crucial roles in modulation of circadian clock function, feeding behavior, and learning memory in insects, detection of neuropeptide receptors is important for understanding the mechanism of GPCR in insect physiological process. Several Drosophila orphan GPCRs were expressed in Xenopus oocyte for selecting the response to various peptides, showing specific function of these orphan GPCRs were receptors for PRXamide, Cap2b-like peptides, crustacean cardioactive peptides, corazonin, or adipokinetic hormone (79). A Drosophila orphan GPCR gene was expression in mammal cells showing selective sensitivity to diuretic hormone and involved in maintaining physiological homeostasis (80). An octopamine receptor was isolated from honey bee brain and the function was determined via expression in human cells and detecting cAMP production in cells (81). The expression of DH-R of silkworm in Xenopus oocyte suggested pivotal function of DH-R in response to diapause hormone and its potential role in silkworm embryonic diapause (53). A large-scale RNAi screen tested the function of GPCR genes in red flour beetle and identified knockdown of these GPCR genes caused severe developmental arrest and ecdysis failure via injection of dsRNA of 111 GPCR genes into one-day-old final instar larvae (82). Knockdown of Methuselah GPCR genes in the red flour beetle showed the functions in regulation of insect lifespan and stress resistance (83). Knockdown of ErGPCR genes in the epidermal cells of corn earworm showed that involved in 20-hydroxyecdysone induced calcium signaling pathway (84). RNA-interference guided functional study in Culex mosquitoes demonstrated 4 GPCR genes, which overexpressed in insecticide resistance mosquitoes, were involved in resistance regulation toward P450 gene expression by showing suppression of these GPCR gene expression not only caused mosquito decreased resistance to insecticide but also resulted in deceased expression of resistance-related P450 genes (10). The downstream effectors in GPCR 162
regulation pathway including G-protein, adenylate cyclase, cAMP, and protein kinase A, all have been identified to be implicated in resistance and P450 gene expression in insecticide resistant Culex mosquitoes via RNAi technique (9, 11). Overexpression of resistance related-GPCR in the D. melanogaster, dramatically increased tolerance of flies to insecticide and overexpression of P450 genes (9). The pivotal function of these effectors in GPCR regulation pathway was further investigated in field resistant strain and insecticide susceptible strain of Culex mosquitoes. Knockdown expression of these effectors in different mosquito strains showed increased susceptibility of mosquitoes to insecticide as well as decreased expression of downstream genes including multiple P450 genes (11). Moreover, in vitro expression of GPCR, G-protein alpha s subunit, adenylate cyclase, protein kinase A in insect Sf9 cell line provided more solid evidence of gene interaction and connection in insecticide resistance. Cell second messenger (cAMP) was identified to be involved in this regulation cascade; as well as resistance-related P450 gene expression was increased corresponding to an increase of each effector expression and tolerance to insecticide in Sf9 cell lines. These findings indicated a universal function of GPCR-led intracellular regulation pathways in insecticide resistance and provide new insight on resistance development in insects.
GPCRs as Targets for the Development of Novel Insecticides In current decade, GPCRs have been studies as targets for the development of new insecticides for pest control, because GPCRs play crucial roles in insect physiological processes and biological behaviors. Current technologies of whole genome sequencing and target site selection screening have significantly increased the efficiency of new insecticide development, in which GPCRs are primary under resource for next generation insecticides (85, 86). Antagonists or agonists of several GPCRs may interfere with insect development, reproduction, even to death (87). For example, the neuropeptide receptors are important in modulating insect reproduction and host seeking behaviors, so it could be utilized as new targets for insecticides in many insect species, such as red flour beetle, pea aphid, drosophila (6) and the brown planthopper (88). The formamidine is one class of insecticides/acaricides that target to the octopamine GPCRs in the control of mites, ticks and some insect species (89). Fuchs et al. (90) reported octopaminergic/tyraminergic signaling is implicated in mosquito oviposition and egg hatching rate, so receptors for these amines provided new targets for insecticides. In Anopheles gambiae, octopamine/tyramine receptors were isolated and virtual screening selected compounds were tested for antagonists/agonists in vitro, suggesting computational and experimental approach is more effective to select new insecticides (91). Recently the dopamine receptor has been studied as target for new chemistries selection in insect species via “Genome-to-Lead” approach (92). For example, two dopamine receptors were identified in the yellow fever mosquitoes and the antagonists/agonists were tested and chemistries were selected via cell-based chemical library screening, identifying several antagonistic effects of selected compounds to dopamine 163
receptor. Subsequently toxicity of these compounds on mosquito larvae caused high mortality for insecticide discovery (93). Similar approaches were utilized in other species and found effectively antagonistic compounds for dopamine receptors in southern house mosquito (94) and tick (95). Methuselah (Mth) GPCR is involved in stress responses and biological aging of D. melanogaster. One nature compound named rediocide A was investigated in desensitization of Mth receptor and the regulation pathway was associated with activation of conventional protein kinase C and calcium mobilization (96). However, some unexpected effects of new developed insecticides targeting GPCRs have been found. For example, these insecticides impact even on beneficial insects, such as honey bee. The biogenic amines-based insecticide that have been reported to disrupt neural cholinergic and octopaminergic signaling transduction so interrupt honey bee foragers back to hives. In this process, octopamine receptor GPCRs as octopamine-based insecticide target are implicated in complicated intracellular responses including induction of reactive oxygen species (ROS), olfactory learning/memory and colony collapse disorder (CCD) (97). In addition, the possibility of resistance increase to new developed insecticides could not be predicted and largely explored. Thus, understanding the mode of action and molecular basis of new insecticide is very critical.
Future Study of GPCRs for Pest Control Although whole genome sequencing has provided the knowledge of diverse GPCRs in insect species, the function of many GPCRs has yet been elucidated. GPCRs are ideal targets for the development of new insecticides for pest control currently, however the underlying mechanism in GPCR regulation pathway is largely unexplored. Additionally, the new insecticides whether will cause rapidly developed resistance is still questionable. Thus, understanding the molecular basis of GPCRs in insecticide resistance will not only provide knowledge to resistance problem but also allow us to develop effective insecticides for pest control in the future. Currently the primary function of a GPCR-regulatory pathway has been investigated in different insect species including mosquito, drosophila, and in insect Sf9 cells. In this regulation pathway, constitutively expressed rhodopsin-like GPCR could regulate downstream intracellular cascades through activating G-protein alpha s-subunit. The active G-protein regulates adenylate cyclase to convert ATP to cAMP. cAMP is critical second messenger in intracellular cascades and increases PKA activity, which is involved in resistance-related P450 gene expression. Inhibitors of cAMP production or PKA activity play synergistic roles to the toxicity of insecticide on mosquito larvae and Sf9 cells, suggesting the potential function of these inhibitors in pest control (9–11, 88) (Figure 2). These exciting discoveries stimulate further exploration of GPCR function in both insecticide resistance management and new insecticide development.
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Conclusion Insecticide resistance has been found in many insect species and the underlying mechanisms of resistance have been studied. Although the cis-/trans-acting factors in insecticide resistance regulation have been found, the specific gene(s) in the intracellular cascades is still largely unknown. Because GPCRs and their regulation pathways play crucial function in insect physiological processes and diverse GPCRs have been identified in insect genome, GPCRs have been studied as targets for the development of new insecticides. Addition to the general concepts of GPCRs in insects, constitutive expressed GPCRs were found to be involved in resistance-related P450 gene expression through intracellular cascades, in which more effectors are identified in this regulation pathway. This study has provided not only the mechanism of gene regulations and interactions involved in resistance, but also a new insight to the development of effectively new insecticides and/or environmentally friendly insecticides for better pest control and resistance management.
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