PMID- 19864434
OWN - NLM
STAT- MEDLINE
DCOM- 20100211
LR  - 20141120
IS  - 1521-0111 (Electronic)
IS  - 0026-895X (Linking)
VI  - 77
IP  - 2
DP  - 2010 Feb
TI  - CCR2 receptor ligands inhibit Cav3.2 T-type calcium channels.
PG  - 211-7
LID - 10.1124/mol.109.059022 [doi]
AB  - Monocyte chemoattractant protein-1 (MCP-1) is a cytokine known to be involved in 
      the recruitment of monocytes to sites of injury. MCP-1 activates the chemokine 
      (C-C motif) receptor 2 (CCR2), a seven-transmembrane helix G protein-coupled 
      receptor that has been implicated in inflammatory pain responses. Here we show 
      that MCP-1 mediates activation of the CCR2 receptor and inhibits coexpressed 
      N-type calcium channels in tsA-201 cells via a voltage-dependent pathway. 
      Moreover, MCP-1 inhibits Ca(v)3.2 calcium channels, but not other members of the 
      Cav3 calcium channel family, with nanomolar affinity. Unlike in N-type channels, 
      this modulation does not require CCR2 receptor activation and seems to involve a 
      direct action of the ligand on the channel. Whole-cell T-type calcium currents in 
      acutely dissociated dorsal root ganglia neurons are effectively inhibited by 
      MCP-1, consistent with the notion that these cells express Ca(v)3.2. The effects 
      of MCP-1 were eliminated by heat denaturation. Furthermore, they were sensitive 
      to the application of the divalent metal ion chelator 
      diethylenetriaminepentaacetic acid, suggesting the possibility that metal ions 
      may act as a cofactor. Finally, small organic CCR2 receptor antagonists inhibit 
      Ca(v)3.2 and other members of the T-type channel family with micromolar affinity. 
      Our findings provide novel avenues for the design of small organic inhibitors of 
      T-type calcium channels for the treatment of pain and other T-type channel linked 
      disorders.
FAU - You, Haitao
AU  - You H
AD  - Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, 
      T2N 4N1, Canada.
FAU - Altier, Christophe
AU  - Altier C
FAU - Zamponi, Gerald W
AU  - Zamponi GW
LA  - eng
GR  - Canadian Institutes of Health Research/Canada
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20091028
PL  - United States
TA  - Mol Pharmacol
JT  - Molecular pharmacology
JID - 0035623
RN  - 0 (CACNA1H protein, human)
RN  - 0 (CCL2 protein, human)
RN  - 0 (Cacna1h protein, rat)
RN  - 0 (Calcium Channel Blockers)
RN  - 0 (Calcium Channels, N-Type)
RN  - 0 (Calcium Channels, T-Type)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Ligands)
RN  - 0 (Receptors, CCR2)
SB  - IM
MH  - Animals
MH  - Calcium Channel Blockers/*metabolism/pharmacology
MH  - Calcium Channels, N-Type/biosynthesis/metabolism
MH  - Calcium Channels, T-Type/*metabolism
MH  - Cell Line
MH  - Chemokine CCL2/metabolism/physiology
MH  - Humans
MH  - Ligands
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptors, CCR2/*metabolism
EDAT- 2009/10/30 06:00
MHDA- 2010/02/12 06:00
CRDT- 2009/10/30 06:00
PHST- 2009/10/30 06:00 [entrez]
PHST- 2009/10/30 06:00 [pubmed]
PHST- 2010/02/12 06:00 [medline]
AID - mol.109.059022 [pii]
AID - 10.1124/mol.109.059022 [doi]
PST - ppublish
SO  - Mol Pharmacol. 2010 Feb;77(2):211-7. doi: 10.1124/mol.109.059022. Epub 2009 Oct 
      28.