The Lipid Kinase PIP5K1C Regulates Pain Signaling and Sensitization

Brittany D. Wright, Lipin Loo, Sarah E. Street, Anqi Ma, Bonnie Taylor-Blake, Michael A. Stashko, Jian Jin, William P. Janzen, Stephen V. Frye, Mark J. Zylka

Research output: Contribution to journalArticlepeer-review

59 Scopus citations

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.

Original languageEnglish
Pages (from-to)836-847
Number of pages12
JournalNeuron
Volume82
Issue number4
DOIs
StatePublished - 21 May 2014
Externally publishedYes

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