Construction of a Global Pain Systems Network Highlights Phospholipid Signaling as a Regulator of Heat Nociception

G. Gregory Neely, Shuan Rao, Michael Costigan, Norbert Mair, Ildiko Racz, Giedre Milinkeviciute, Arabella Meixner, Swetha Nayanala, Robert S. Griffin, Inna Belfer, Feng Dai, Shad Smith, Luda Diatchenko, Stefano Marengo, Bernhard J. Haubner, Maria Novatchkova, Dustin Gibson, William Maixner, J. Andrew Pospisilik, Emilio HirschIan Q. Whishaw, Andreas Zimmer, Vaijayanti Gupta, Junko Sasaki, Yasunori Kanaho, Takehiko Sasaki, Michaela Kress, Clifford J. Woolf, Josef M. Penninger

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article numbere1003071
JournalPLoS genetics
Volume8
Issue number12
DOIs
StatePublished - Dec 2012

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

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