PMID- 26010461
OWN - NLM
STAT- MEDLINE
DCOM- 20160503
LR  - 20220316
IS  - 1098-1136 (Electronic)
IS  - 0894-1491 (Linking)
VI  - 63
IP  - 10
DP  - 2015 Oct
TI  - Activation of mitochondrial transient receptor potential vanilloid 1 channel 
      contributes to microglial migration.
PG  - 1870-82
LID - 10.1002/glia.22854 [doi]
AB  - Microglia, the resident immune cells in the brain, survey the environment of the 
      healthy brain. Microglial migration is essential for many physiological and 
      pathophysiological processes. Although microglia express some members of the 
      transient receptor potential (TRP) channel family, there is little knowledge 
      regarding the physiological roles of TRP channels in microglia. Here, we explored 
      the role of TRP vanilloid 1 (TRPV1), a channel opened by capsaicin, heat, 
      protons, and endovanilloids, in microglia. We found that application of capsaicin 
      induced concentration-dependent migration in microglia derived from wild-type 
      mice but not in those derived from TRPV1 knockout (TRPV1-KO) mice. 
      Capsaicin-induced microglial migration was significantly inhibited by 
      co-application of the TRPV1 blocker SB366791 and the Ca(2+) chelator BAPTA-AM. 
      Using RT-PCR and immunocytochemistry, we validated that TRPV1 was expressed in 
      microglia. Electrophysiological recording, intracellular Ca(2+) imaging, and 
      immunocytochemistry indicated that TRPV1 was localized primarily in intracellular 
      organelles. Treatment with capsaicin induced an increase in intramitochondrial 
      Ca(2+) concentrations and mitochondrial depolarization. Furthermore, microglia 
      derived from TRPV1-KO mice showed delayed Ca(2+) efflux compared with microglia 
      derived from wild-type mice. Capsaicin-induced microglial migration was inhibited 
      by membrane-permeable antioxidants and MAPK inhibitors, suggesting that 
      mitochondrial TRPV1 activation induced Ca(2+) -dependent production of ROS 
      followed by MAPK activation, which correlated with an augmented migration of 
      microglia. Moreover, a mixture of three endovanilloids augmented microglial 
      migration via TRPV1 activation. Together, these results indicate that 
      mitochondrial TRPV1 plays an important role in inducing microglial migration. 
      Activation of TRPV1 triggers an increase in intramitochondrial Ca(2+) 
      concentration and following depolarization of mitochondria, which results in 
      mtROS production, MAPK activation, and enhancement of chemotactic activity in 
      microglia.
CI  - (c) 2015 Wiley Periodicals, Inc.
FAU - Miyake, Takahito
AU  - Miyake T
AD  - Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, 
      Kyoto University, Kyoto, Japan.
FAU - Shirakawa, Hisashi
AU  - Shirakawa H
AD  - Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, 
      Kyoto University, Kyoto, Japan.
FAU - Nakagawa, Takayuki
AU  - Nakagawa T
AD  - Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, 
      Kyoto University, Kyoto, Japan.
AD  - Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, 
      Kyoto, Japan.
FAU - Kaneko, Shuji
AU  - Kaneko S
AD  - Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, 
      Kyoto University, Kyoto, Japan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150523
PL  - United States
TA  - Glia
JT  - Glia
JID - 8806785
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Interleukin-6)
RN  - 0 (Sensory System Agents)
RN  - 0 (TRPV Cation Channels)
RN  - 0 (TRPV1 protein, mouse)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 169D1260KM (Nitroprusside)
RN  - EC 2.7.12.2 (MAP Kinase Kinase 4)
RN  - S07O44R1ZM (Capsaicin)
SB  - IM
MH  - Animals
MH  - Animals, Newborn
MH  - Capsaicin/pharmacology
MH  - Cell Movement/drug effects/*physiology
MH  - Cells, Cultured
MH  - Enzyme Inhibitors/pharmacology
MH  - HEK293 Cells
MH  - Humans
MH  - Interleukin-6/metabolism
MH  - MAP Kinase Kinase 4/metabolism
MH  - Membrane Potential, Mitochondrial/drug effects/genetics
MH  - Membrane Potentials/drug effects/genetics
MH  - Mice
MH  - Mice, Knockout
MH  - Microglia/*physiology/ultrastructure
MH  - Mitochondria/drug effects/metabolism
MH  - Nitroprusside/metabolism
MH  - Sensory System Agents/pharmacology
MH  - TRPV Cation Channels/genetics/*metabolism
MH  - Tumor Necrosis Factor-alpha/metabolism
OTO - NOTNLM
OT  - Ca2+ signaling
OT  - TRPV1
OT  - cell movement
OT  - microglia
OT  - mitochondria
EDAT- 2015/05/27 06:00
MHDA- 2016/05/04 06:00
CRDT- 2015/05/27 06:00
PHST- 2014/11/27 00:00 [received]
PHST- 2015/04/17 00:00 [accepted]
PHST- 2015/05/27 06:00 [entrez]
PHST- 2015/05/27 06:00 [pubmed]
PHST- 2016/05/04 06:00 [medline]
AID - 10.1002/glia.22854 [doi]
PST - ppublish
SO  - Glia. 2015 Oct;63(10):1870-82. doi: 10.1002/glia.22854. Epub 2015 May 23.