[Abstract Title]. - Society for Neuroscience

Topic: D.08.a. Pain transduction molecules and channels
Title: Involvement of c-src kinase, PLCγ1, and PKC in the acute sensitization of TRPV1 by
artemin
Authors: *W. ZHU 1 , G. OXFORD 2 ;
1 Dept Pharmacol & Toxicol, 2 Stark Neurosciences Res. Inst., Indiana Univ. Schl Med.,
Indianapolis, IN
Abstract: Acute sensitization of TRPV1 by inflammatory mediators, like nerve growth factor
(NGF) or activin, contribute significantly to hypersensitivity of nociceptors, which underlie the
induction and maintenance of persistent pain associated with inflammation or injury. Recent
studies indicate that another neurotrophic factor artemin (ARTN), a member of the glial cell
derived neurotrophic factor (GDNF) family of ligands, can acutely sensitize TRPV1 in cultured
DRG neurons and can induce thermal hyperalgesia after injection into the animal paw. While
ARTN and NGF are likely to exert their actions on the same subset of DRG neurons, whether
they use the same signaling pathways to sensitize TRPV1 is unknown. We combined patch
clamp electrophysiology and pharmacology to explore the signaling pathways underlying
TRPV1 sensitization by ARTN in cultured adult rat DRG neurons. ARTN acutely sensitized
capsaicin-induced current in ~70% of recorded neurons. Unlike NGF, ARTN acutely sensitizes
TRPV1 when neurons were pre-treated with the MEK specific inhibitor U0126 (5 µM), or the
PI3K specific inhibitor wortmannin (100 nM), despite their biochemically verified inhibition of
p-ERK and p-Akt, respectively. In contrast, inhibition of c-src kinase by PP2 (10 µM), of PLCγ1
by U73122 (10 µM), or of PKC (1 µM) by BIM, all abrogated acute sensitization of TRPV1 by
ARTN. These data suggest that activation of c-src kinase, PLCγ1 and PKC are implicated to
acute sensitization of TRPV1 by ARTN, whereas Erk1/2 and PI3K are not involved. We
conclude that although NGF and ARTN both acutely sensitize TRPV1 through binding to their
respective neurotrophic receptors (TrkA and GFRα3-RET), the post-receptor signaling cascades
for each ligand are distinct.
Disclosures: W. Zhu , None; G. Oxford, None.
Poster
265. Nociceptors II
Time: Sunday, November 16, 2008, 1:00 pm - 5:00 pm
Program#/Poster#: 265.19/EE20
Topic: B.02.t. TRP Channels
Title: TRPM2 inhibits neurite outgrowth via LPA receptor