Escape steering by cholecystokinin peptidergic signaling

Chen, Lili; Liu, Yuting; S, Pan; Hung, Wesley; Li, Haiwen; Wang, Ya; Yue, Zhongpu; Ge, Minghai; Wu, Zheng-Xing; Zhang, Yan; Fei, Peng; Chen, Liming; Tao, Louis; Zhen, Mei; Gao, Shangbang

doi:10.1016/j.celrep.2022.110330

Cited by 13 publications

(25 citation statements)

References 84 publications

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“…In the last decades, reverse pharmacology has proven to be a successful approach for the deorphanization of GPCRs, by expressing receptors in heterologous cells and identifying their ligand(s) in a compound library 44 . This way, a broad range of peptide GPCRs have been deorphanized, including at least 138 receptors in humans, 36 in Drosophila melanogaster, and 29 in Caenorhabditis elegans 40,[45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61] . Nevertheless, many peptide GPCRs remain orphan receptors, hampering investigations into their functions 62 .…”

Section: Introductionmentioning

confidence: 99%

System-wide mapping of neuropeptide-GPCR interactions inC. elegans

Beets¹,

Zels²,

Vandewyer³

et al. 2022

Preprint

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Neuropeptides are ancient, widespread signaling molecules that underpin almost all brain functions. They constitute a broad ligand-receptor network, mainly by binding to G protein-coupled receptors (GPCRs). However, the organization of the peptidergic network and roles of many neuropeptides remain elusive, as our insight into neuropeptide-receptor interactions is limited and many peptide GPCRs in animal models and humans are still orphan receptors. Here we report a genome-wide neuropeptide-GPCR interaction map in C. elegans. By reverse pharmacology screening of over 55,384 possible interactions, we identify 461 cognate peptide-GPCR couples that uncover a broad signaling network with specific and complex combinatorial interactions encoded across and within single peptidergic genes. These interactions provide insights into neuropeptide functions and evolution. Combining our dataset with phylogenetic analysis supports peptide-receptor co-evolution and conservation of at least 14 bilaterian peptidergic systems in C. elegans. This resource lays a foundation for system-wide analysis of the peptidergic network.

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Section: Introductionmentioning

confidence: 99%

System-wide mapping of neuropeptide-GPCR interactions inC. elegans

Beets¹,

Zels²,

Vandewyer³

et al. 2022

Preprint

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“…The fact that CGRP and CCK neurons are spatially segregated, responsive to distinct threat signals and involved in different defensive responses, indicating that LPB acts as an important integration center or hub to gate defensive responses when animals encounter different threats (S. Liu et al, 2022;Tokita, Inoue, & Boughter Jr, 2009). It would be interesting to investigate whether LPB CCK and LPB CGRP neurons coordinately regulate defensive responses under different threatening situations.…”

Section: Hippocampal and Cortical Cck-expressing Neurons Have Been Th...mentioning

confidence: 99%

“…Both CCK and CCK receptor-expressing neurons have been implicated in defensive behaviors (Bertoglio, de Bortoli, & Zangrossi, 2007;Chen et al, 2022; W.…”

Section: Introductionmentioning

confidence: 99%

“…Both CCK and CCK receptor-expressing neurons have been implicated in defensive behaviors (Bertoglio, de Bortoli, & Zangrossi, 2007; Chen et al, 2022; W. Wang, P. J. Schuette, M. Q. La-Vu, et al, 2021). PVN neurons also express CCK receptors and are involved in defensive behaviors (Mangieri et al, 2019a; O’Shea & Gundlach, 1993; Xu et al, 2019), raising a possibility that upstream CCK inputs to the PVN (Meister, Broberger, Villar, & Hökfelt, 1994) may be implicated in defensive behaviors.…”

Section: Introductionmentioning

confidence: 99%

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A Parabrachial to Hypothalamic Pathway Mediates Defensive Behavior

Wang

Chen

Lin

et al. 2022

Preprint

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Defensive behaviors are critical for animal’s survival. The parabrachial nucleus (PBN) is critical in transmitting danger stimuli to trigger behavioral responses. Here, by viral tracing and electrophysiological recordings, we uncover that cholecystokinin (CCK) neurons in the lateral PB (LPBCCK neurons) are monosynaptic connected with the paraventricular nucleus (PVN) neurons. Selective photoactivation of LPBCCK neurons, their axon terminals within the PVN and glutamatergic neurons in the PVN, trigger defensive-like flight-to-nest behavior. Conversely, photoinhibition of LPBCCK neurons suppresses defensive responses. We show that LPBCCK neurons provide excitatory transmission to the PVN neurons and blocking glutamatergic transmission inhibits LPBCCK-PVN pathway activation-induced flight behaviors. Further, we demonstrate that chemogenetic inhibition of PVN neurons prevents photoactivation of LPBCCK-PVN pathway-driven flight responses. These data suggest that LPBCCK neurons recruit downstream PVN neurons to actively engage in flight responses. Our study identifies a novel circuit from LPBCCK to PVN and dissects its role in defensive behaviors.

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“…We do not have widely accessible and reliable tools to predict the structural similarity among small secreted proteins. Indeed, while amino acid sequences for the bulk of the C. elegans neuropeptides revealed no homologs, thus deemed 'nematode-specific', several have been shown to bind and activate evolutionarily conserved GPCR signaling and to serve homologous physiological functions 66,67 .…”

Section: Potential Physiological Functions Of C54f65mentioning

confidence: 99%

Two Muscle-Specific and Direct Transcriptional Targets of DAF-16/FOXO Activated by Reduced Insulin/IGF-1 Signaling

Roy

et al. 2022

Preprint

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C. elegansinsulin/insulin-like growth factor 1 signaling (IIS) affects diverse physiological processes through the DAF-16/FOXO transcription factor. Despite its presence in all somatic cells, DAF-16's physiological effects, such as modulation of dauer formation, synapse maturation, axon regeneration, and adult longevity, exhibit prevalent tissue-specificity as well as tissue crosstalk. This implies that tissue-specific DAF-16 transcriptional programs contribute to the functional diversity of IIS. To further examine this possibility, we sought to identify tissue-specific and direct transcriptional targets of DAF-16 in muscle cells. Following FACS-sorting to enrich mature muscle cells from young adult animals, we compared the muscle transcriptomes under high and low IIS signaling conditions, with and without DAF-16. We further analyzed and compared the DAF-16 docking sites in muscle and intestine cells from published datasets. These analyses revealed 14 potential muscle-specific DAF-16 transcriptional targets, among which we validated two that are strongly and specifically activated by DAF-16 in muscles: a secreted protein C54F6.5 and a calcium-binding protein CEX-1/Calexcitin. Both genes exhibit DAF-16-independent non-muscle expression, explaining their low rank or absence from the current DAF-16 target lists generated by multiple independent whole-animal microarray or mRNA-sequencing analyses. These results support the notion of tissue-specific DAF-16 transcriptional programs and highlight the importance of verifying FOXO targets in a cell-type-specific manner.

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Escape steering by cholecystokinin peptidergic signaling

Cited by 13 publications

References 84 publications

System-wide mapping of neuropeptide-GPCR interactions inC. elegans

System-wide mapping of neuropeptide-GPCR interactions inC. elegans

A Parabrachial to Hypothalamic Pathway Mediates Defensive Behavior

Two Muscle-Specific and Direct Transcriptional Targets of DAF-16/FOXO Activated by Reduced Insulin/IGF-1 Signaling

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