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

• DOI: 10.1371/journal.pgen.1003071
• Publication Date: 2012-12-06T21:51:59Z
• Authors: G. Gregory Neely; Shuan Rao; Michael Costigan; Norbert Mair; Ildiko Racz; Giedre Milinkevic...; 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 Hirsch; Ian Q. Whishaw; Andreas Zimmer; Vaijayanti Gupta; Junko Sasaki; Yasunori Kanaho; Takehiko Sasaki; Michaela Kress; Clifford J. Woolf; Josef M. Penninger
• Keywords: Nociception; 0301 basic medicine; 570; Hot Temperature; Mouse; Cognitive Neuroscience; Pain; 610; TRPV Cation Channels; QH426-470; Signaling Pathways; Nociceptive Pain; Behavioral Neuroscience; Mice; 03 medical and health sciences; Model Organisms; Genetics; Hypersensitivity; Animals; Class Ib Phosphatidylinositol 3-Kinase; Humans; pain; Gene Regulatory Networks; Neurons, Afferent; Biology; Phospholipids; Drosophila Melanogaster; Genomics; Animal Models; Sensory Systems; Functional Genomics; Phosphotransferases (Alcohol Group Acceptor); Sensory Perception; Drosophila; Molecular Neuroscience; Capsaicin; Pain sensation; Neuroscience; Research Article; Signal Transduction

The ability to perceive noxious stimuli is critical for an animal's survival in the face of environmental danger, and thus pain perception likely be under stringent evolutionary pressure. Using a neuronal-specific RNAi knock-down strategy adult Drosophila, we recently completed genome-wide functional annotation heat nociception that allowed us identify α2δ3 as novel gene. Here report construction evolutionary-conserved, system-level, global molecular network map. Our systems map markedly enriched multiple genes associated with human predicts plethora candidate pathways. One central node this phospholipid signaling, which has been implicated before processing. To further investigate role signaling mammalian perception, analysed phenotype PIP5Kα PI3Kγ mutant mice. Intriguingly, both these mice exhibit pronounced hypersensitivity capsaicin-induced pain, directly mapped through kinase-dead knock-in lipid kinase activity. single primary sensory neuron recording, function was mechanistically linked negative regulation TRPV1 channel transduction. data provide reinforces extraordinary conservation mechanisms across different species.