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The lipid kinase PIP5K1C regulates pain signaling and sensitization.
Wright, Brittany D; Loo, Lipin; Street, Sarah E; Ma, Anqi; Taylor-Blake, Bonnie; Stashko, Michael A; Jin, Jian; Janzen, William P; Frye, Stephen V; Zylka, Mark J.
Afiliación
  • Wright BD; Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Cell Biology and Physiology, UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Loo L; Department of Cell Biology and Physiology, UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Street SE; Department of Cell Biology and Physiology, UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Ma A; Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Center for Integrative Chemical Biology and Drug Discovery, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Taylor-Blake B; Department of Cell Biology and Physiology, UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Stashko MA; Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Center for Integrative Chemical Biology and Drug Discovery, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Jin J; Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Center for Integrative Chemical Biology and Drug Discovery, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Janzen WP; Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Center for Integrative Chemical Biology and Drug Discovery, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Frye SV; Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Center for Integrative Chemical Biology and Drug Discovery, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Zylka MJ; Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Cell Biology and Physiology, UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Neuron ; 82(4): 836-47, 2014 May 21.
Article en En | MEDLINE | ID: mdl-24853942
ABSTRACT
Numerous pain-producing (pronociceptive) receptors signal via phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis. However, it is currently unknown which lipid kinases generate PIP2 in nociceptive dorsal root ganglia (DRG) neurons and if these kinases regulate pronociceptive receptor signaling. Here, we found that phosphatidylinositol 4-phosphate 5 kinase type 1C (PIP5K1C) is expressed at higher levels than any other PIP5K and, based on experiments with Pip5k1c(+/-) mice, generates at least half of all PIP2 in DRG neurons. Additionally, Pip5k1c haploinsufficiency reduces pronociceptive receptor signaling and TRPV1 sensitization in DRG neurons as well as thermal and mechanical hypersensitivity in mouse models of chronic pain. We identified a small molecule inhibitor of PIP5K1C (UNC3230) in a high-throughput screen. UNC3230 lowered PIP2 levels in DRG neurons and attenuated hypersensitivity when administered intrathecally or into the hindpaw. Our studies reveal that PIP5K1C regulates PIP2-dependent nociceptive signaling and suggest that PIP5K1C is a therapeutic target for chronic pain.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Umbral del Dolor / Fosfotransferasas (Aceptor de Grupo Alcohol) / Hiperalgesia Límite: Animals Idioma: En Revista: Neuron Asunto de la revista: NEUROLOGIA Año: 2014 Tipo del documento: Article País de afiliación: Estados Unidos
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Umbral del Dolor / Fosfotransferasas (Aceptor de Grupo Alcohol) / Hiperalgesia Límite: Animals Idioma: En Revista: Neuron Asunto de la revista: NEUROLOGIA Año: 2014 Tipo del documento: Article País de afiliación: Estados Unidos