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Construction of a Global Pain Systems Network Highlights Phospholipid Signaling as a Regulator of Heat Nociception
The ability to perceive noxious stimuli is critical for an animal's survival in the face of environmental danger, and thus pain perception is likely to be under stringent evolutionary pressure. Using a neuronal-specific RNAi knock-down strategy in adult Drosophila, we recently completed a genom...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3516557/ https://www.ncbi.nlm.nih.gov/pubmed/23236288 http://dx.doi.org/10.1371/journal.pgen.1003071 |
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author | Neely, G. Gregory Rao, Shuan Costigan, Michael Mair, Norbert Racz, Ildiko Milinkeviciute, Giedre Meixner, Arabella Nayanala, Swetha Griffin, Robert S. Belfer, Inna Dai, Feng Smith, Shad Diatchenko, Luda Marengo, Stefano Haubner, Bernhard J. Novatchkova, Maria Gibson, Dustin Maixner, William Pospisilik, J. Andrew Hirsch, Emilio Whishaw, Ian Q. Zimmer, Andreas Gupta, Vaijayanti Sasaki, Junko Kanaho, Yasunori Sasaki, Takehiko Kress, Michaela Woolf, Clifford J. Penninger, Josef M. |
author_facet | Neely, G. Gregory Rao, Shuan Costigan, Michael Mair, Norbert Racz, Ildiko Milinkeviciute, Giedre Meixner, Arabella Nayanala, Swetha Griffin, Robert S. Belfer, Inna Dai, Feng Smith, Shad Diatchenko, Luda Marengo, Stefano Haubner, Bernhard J. Novatchkova, Maria Gibson, Dustin Maixner, William Pospisilik, J. Andrew Hirsch, Emilio Whishaw, Ian Q. Zimmer, Andreas Gupta, Vaijayanti Sasaki, Junko Kanaho, Yasunori Sasaki, Takehiko Kress, Michaela Woolf, Clifford J. Penninger, Josef M. |
author_sort | Neely, G. Gregory |
collection | PubMed |
description | The ability to perceive noxious stimuli is critical for an animal's survival in the face of environmental danger, and thus pain perception is likely to be under stringent evolutionary pressure. Using a neuronal-specific RNAi knock-down strategy in adult Drosophila, we recently completed a genome-wide functional annotation of heat nociception that allowed us to identify α2δ3 as a novel pain gene. Here we report construction of an evolutionary-conserved, system-level, global molecular pain network map. Our systems map is markedly enriched for multiple genes associated with human pain and predicts a plethora of novel candidate pain pathways. One central node of this pain network is phospholipid signaling, which has been implicated before in pain processing. To further investigate the role of phospholipid signaling in mammalian heat pain perception, we analysed the phenotype of PIP5Kα and PI3Kγ mutant mice. Intriguingly, both of these mice exhibit pronounced hypersensitivity to noxious heat and capsaicin-induced pain, which directly mapped through PI3Kγ kinase-dead knock-in mice to PI3Kγ lipid kinase activity. Using single primary sensory neuron recording, PI3Kγ function was mechanistically linked to a negative regulation of TRPV1 channel transduction. Our data provide a systems map for heat nociception and reinforces the extraordinary conservation of molecular mechanisms of nociception across different species. |
format | Online Article Text |
id | pubmed-3516557 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-35165572012-12-12 Construction of a Global Pain Systems Network Highlights Phospholipid Signaling as a Regulator of Heat Nociception Neely, G. Gregory Rao, Shuan Costigan, Michael Mair, Norbert Racz, Ildiko Milinkeviciute, Giedre Meixner, Arabella Nayanala, Swetha Griffin, Robert S. Belfer, Inna Dai, Feng Smith, Shad Diatchenko, Luda Marengo, Stefano Haubner, Bernhard J. Novatchkova, Maria Gibson, Dustin Maixner, William Pospisilik, J. Andrew Hirsch, Emilio Whishaw, Ian Q. Zimmer, Andreas Gupta, Vaijayanti Sasaki, Junko Kanaho, Yasunori Sasaki, Takehiko Kress, Michaela Woolf, Clifford J. Penninger, Josef M. PLoS Genet Research Article The ability to perceive noxious stimuli is critical for an animal's survival in the face of environmental danger, and thus pain perception is likely to be under stringent evolutionary pressure. Using a neuronal-specific RNAi knock-down strategy in adult Drosophila, we recently completed a genome-wide functional annotation of heat nociception that allowed us to identify α2δ3 as a novel pain gene. Here we report construction of an evolutionary-conserved, system-level, global molecular pain network map. Our systems map is markedly enriched for multiple genes associated with human pain and predicts a plethora of novel candidate pain pathways. One central node of this pain network is phospholipid signaling, which has been implicated before in pain processing. To further investigate the role of phospholipid signaling in mammalian heat pain perception, we analysed the phenotype of PIP5Kα and PI3Kγ mutant mice. Intriguingly, both of these mice exhibit pronounced hypersensitivity to noxious heat and capsaicin-induced pain, which directly mapped through PI3Kγ kinase-dead knock-in mice to PI3Kγ lipid kinase activity. Using single primary sensory neuron recording, PI3Kγ function was mechanistically linked to a negative regulation of TRPV1 channel transduction. Our data provide a systems map for heat nociception and reinforces the extraordinary conservation of molecular mechanisms of nociception across different species. Public Library of Science 2012-12-06 /pmc/articles/PMC3516557/ /pubmed/23236288 http://dx.doi.org/10.1371/journal.pgen.1003071 Text en © 2012 Neely et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Neely, G. Gregory Rao, Shuan Costigan, Michael Mair, Norbert Racz, Ildiko Milinkeviciute, Giedre Meixner, Arabella Nayanala, Swetha Griffin, Robert S. Belfer, Inna Dai, Feng Smith, Shad Diatchenko, Luda Marengo, Stefano Haubner, Bernhard J. Novatchkova, Maria Gibson, Dustin Maixner, William Pospisilik, J. Andrew Hirsch, Emilio Whishaw, Ian Q. Zimmer, Andreas Gupta, Vaijayanti Sasaki, Junko Kanaho, Yasunori Sasaki, Takehiko Kress, Michaela Woolf, Clifford J. Penninger, Josef M. Construction of a Global Pain Systems Network Highlights Phospholipid Signaling as a Regulator of Heat Nociception |
title | Construction of a Global Pain Systems Network Highlights Phospholipid Signaling as a Regulator of Heat Nociception |
title_full | Construction of a Global Pain Systems Network Highlights Phospholipid Signaling as a Regulator of Heat Nociception |
title_fullStr | Construction of a Global Pain Systems Network Highlights Phospholipid Signaling as a Regulator of Heat Nociception |
title_full_unstemmed | Construction of a Global Pain Systems Network Highlights Phospholipid Signaling as a Regulator of Heat Nociception |
title_short | Construction of a Global Pain Systems Network Highlights Phospholipid Signaling as a Regulator of Heat Nociception |
title_sort | construction of a global pain systems network highlights phospholipid signaling as a regulator of heat nociception |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3516557/ https://www.ncbi.nlm.nih.gov/pubmed/23236288 http://dx.doi.org/10.1371/journal.pgen.1003071 |
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