title: Construction of a global pain systems network highlights phospholipid signaling as a regulator of heat nociception.
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.
authors.affiliation: Neuroscience Program, Garvan Institute of Medical Research, Sydney, New South Wales, Australia. g.neely@garvan.org.au
authors.forename: G Gregory
authors.initials: GG
authors.lastname: Neely
authors.forename: Shuan
authors.initials: S
authors.lastname: Rao
authors.forename: Michael
authors.initials: M
authors.lastname: Costigan
authors.forename: Norbert
authors.initials: N
authors.lastname: Mair
authors.forename: Ildiko
authors.initials: I
authors.lastname: Racz
authors.forename: Giedre
authors.initials: G
authors.lastname: Milinkeviciute
authors.forename: Arabella
authors.initials: A
authors.lastname: Meixner
authors.forename: Swetha
authors.initials: S
authors.lastname: Nayanala
authors.forename: Robert S
authors.initials: RS
authors.lastname: Griffin
authors.forename: Inna
authors.initials: I
authors.lastname: Belfer
authors.forename: Feng
authors.initials: F
authors.lastname: Dai
authors.forename: Shad
authors.initials: S
authors.lastname: Smith
authors.forename: Luda
authors.initials: L
authors.lastname: Diatchenko
authors.forename: Stefano
authors.initials: S
authors.lastname: Marengo
authors.forename: Bernhard J
authors.initials: BJ
authors.lastname: Haubner
authors.forename: Maria
authors.initials: M
authors.lastname: Novatchkova
authors.forename: Dustin
authors.initials: D
authors.lastname: Gibson
authors.forename: William
authors.initials: W
authors.lastname: Maixner
authors.forename: J Andrew
authors.initials: JA
authors.lastname: Pospisilik
authors.forename: Emilio
authors.initials: E
authors.lastname: Hirsch
authors.forename: Ian Q
authors.initials: IQ
authors.lastname: Whishaw
authors.forename: Andreas
authors.initials: A
authors.lastname: Zimmer
authors.forename: Vaijayanti
authors.initials: V
authors.lastname: Gupta
authors.forename: Junko
authors.initials: J
authors.lastname: Sasaki
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Kanaho
authors.forename: Takehiko
authors.initials: T
authors.lastname: Sasaki
authors.forename: Michaela
authors.initials: M
authors.lastname: Kress
authors.forename: Clifford J
authors.initials: CJ
authors.lastname: Woolf
authors.forename: Josef M
authors.initials: JM
authors.lastname: Penninger
mesh_terms: D000818:Animals; D002211:Capsaicin / Q000633:toxicity; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000502:physiology; D004330:Drosophila / Q000235:genetics / Q000502:physiology; D053263:Gene Regulatory Networks; D006358:Hot Temperature; D006801:Humans; D006967:Hypersensitivity / Q000235:genetics; D051379:Mice; D009475:Neurons, Afferent / Q000378:metabolism; D059226:Nociceptive Pain / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology; D010743:Phospholipids / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism / Q000502:physiology
chemical_list: D010743:Phospholipids; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D017853:Phosphotransferases (Alcohol Group Acceptor); D058544:Class Ib Phosphatidylinositol 3-Kinase; C546764:Pik3cg protein, mouse; C020077:1-phosphatidylinositol-4-phosphate 5-kinase; D002211:Capsaicin