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The Journal of Neuroscience, October 21, 2009, 29(42):13377-13388; doi:10.1523/JNEUROSCI.1127-09.2009

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Cellular/Molecular
Proteomic Analysis Uncovers Novel Actions of the Neurosecretory Protein VGF in Nociceptive Processing

Maureen S. Riedl,¹ Patrick D. Braun,^1,2 Kelley F. Kitto,^1,2,3 Samuel A. Roiko,³ Lorraine B. Anderson,⁴ Christopher N. Honda,¹ Carolyn A. Fairbanks,^1,2,3 and Lucy Vulchanova⁵

Departments of ¹Neuroscience, ²Pharmaceutics, ³Pharmacology, and ⁴Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota 55455, and ⁵Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, Minnesota 55108

Correspondence should be addressed to Lucy Vulchanova, Department of Veterinary and Biomedical Sciences, University of Minnesota, 295 AS/VM, 1988 Fitch Avenue, St. Paul, MN 55108. Email: vulch001{at}umn.edu

Peripheral tissue injury is associated with changes in protein expression in sensory neurons that may contribute to abnormal nociceptive processing. We used cultured dorsal root ganglion (DRG) neurons as a model of axotomized neurons to investigate early changes in protein expression after nerve injury. Comparing protein levels immediately after DRG dissociation and 24 h later by proteomic differential expression analysis, we found a substantial increase in the levels of the neurotrophin-inducible protein VGF (nonacronymic), a putative neuropeptide precursor. In a rodent model of nerve injury, VGF levels were increased within 24 h in both injured and uninjured DRG neurons, and the increase persisted for at least 7 d. VGF was also upregulated 24 h after hindpaw inflammation. To determine whether peptides derived from proteolytic processing of VGF participate in nociceptive signaling, we examined the spinal effects of AQEE-30 and LQEQ-19, potential proteolytic products shown previously to be bioactive. Each peptide evoked dose-dependent thermal hyperalgesia that required activation of the mitogen-activated protein kinase p38. In addition, LQEQ-19 induced p38 phosphorylation in spinal microglia when injected intrathecally and in the BV-2 microglial cell line when applied in vitro. In summary, our results demonstrate rapid upregulation of VGF in sensory neurons after nerve injury and inflammation and activation of microglial p38 by VGF peptides. Therefore, VGF peptides released from sensory neurons may participate in activation of spinal microglia after peripheral tissue injury.

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Received March 9, 2009; revised July 15, 2009; accepted Aug. 10, 2009.

Correspondence should be addressed to Lucy Vulchanova, Department of Veterinary and Biomedical Sciences, University of Minnesota, 295 AS/VM, 1988 Fitch Avenue, St. Paul, MN 55108. Email: vulch001{at}umn.edu

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