Journal
ACS OMEGA
Volume 5, Issue 50, Pages 32183-32194Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsomega.0c03382
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Funding
- European Cooperation in Science and Technology (COST) Action CM1207 GPCR-Ligand Interactions, Structures, and Transmembrane Signaling
- European Research Network on Signal Transduction (ERNEST) [CA18133]
- Bogazici University [5043]
- Scientific and Technological Research Council of Turkey [113Z079]
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G protein-coupled receptors (GPCRs) play a pivotal role in regulating key physiological events in all animal species. Recent advances in collective analysis of genes and proteins revealed numerous potential neuro-peptides and GPCRs from insect species, allowing for the characterization of peptide-receptor pairs. In this work, we used fluorescence resonance energy transfer (FRET)-based genetically encoded biosensors in intact mammalian cells to study the pharmacological features of the cognate GPCR of the type-C allatostatin (AST-C) peptide from the stick insect, Carausius morosus. Analysis of multiple downstream pathways revealed that AST-C can activate the human Gi(2) protein, and not Gs or Gq, through AST-C receptor (AIstRC). Activated AlstRC recruits beta-arrestin2 independent of the Gi protein but stimulates ERK phosphorylation in a Gi protein-dependent manner. Identification of G alpha i-, arrestin-, and GRK-like transcripts from C. morosus revealed high evolutionary conservation at the G protein level, while beta-arrestins and GRKs displayed less conservation. In conclusion, our study provides experimental and homology-based evidence on the functionality of vertebrate G proteins and downstream signaling biosensors to characterize early signaling steps of an insect GPCR. These results may serve as a scaffold for developing assays to characterize pharmacological and structural aspects of other insect GPCRs and can be used in deorphanization and pesticide studies.
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