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PMID: 24853942 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

The lipid kinase PIP5K1C regulates pain signaling and sensitization.

Neuron ·Vol. 82 ·No. 4 ·2014-05-21 ·Pages 836-47

Wright BD, Loo L, Street SE, Ma A, Taylor-Blake B, Stashko MA, Jin J, Janzen WP, Frye SV, Zylka MJ

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.

MeSH Terms
Animals Calcitonin Gene-Related Peptide/metabolism Cells, Cultured Disease Models, Animal Enzyme Inhibitors/pharmacology Excitatory Postsynaptic Potentials/genetics Ganglia, Spinal/cytology Hyperalgesia/chemically induced,drug therapy,metabolism In Vitro Techniques Male Mice Mice, Inbred C57BL Mice, Knockout Pain Measurement/drug effects Pain Threshold/drug effects,physiology Phosphatidylinositol 4,5-Diphosphate/metabolism Phosphopyruvate Hydratase/metabolism Phosphotransferases (Alcohol Group Acceptor)/genetics,metabolism Reaction Time/genetics Sensory Receptor Cells/physiology Spinal Cord/cytology
Chemicals
Enzyme Inhibitors Phosphatidylinositol 4,5-Diphosphate Phosphotransferases (Alcohol Group Acceptor) 1-phosphatidylinositol-4-phosphate 5-kinase Phosphopyruvate Hydratase Calcitonin Gene-Related Peptide
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Wright Brittany D
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 Lipin
Department of Cell Biology and Physiology, UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Street Sarah E
Department of Cell Biology and Physiology, UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Ma Anqi
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 Bonnie
Department of Cell Biology and Physiology, UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Stashko Michael 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.
Jin Jian
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 William P
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 Stephen V
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 Mark 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; Department of Cell Biology and Physiology, UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: [email protected].
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Article Info
Journal
Neuron
Abbr.
Neuron
ISSN
1097-4199
DOI
10.1016/j.neuron.2014.04.006
Email
[email protected]
Published
2014-05-21
Pages
836-47
Language
English
Region
United States
NLM ID
8809320
PMCID
PMC4074510
Subset
IM
Grants
NINDS NIH HHS · R01 NS081127 · United States
NINDS NIH HHS · P30 NS045892 · United States
NINDS NIH HHS · R01NS081127 · United States
NICHD NIH HHS · P30 HD003110 · United States
NINDS NIH HHS · P30NS045892 · United States
NINDS NIH HHS · R01 NS067688 · United States
NINDS NIH HHS · R01NS067688 · United States
NICHD NIH HHS · P30HD03110 · United States
External Links
PubMed source DOI: 10.1016/j.neuron.2014.04.006 PMC Full Text View journal details
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