Abstract
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 Cav3.2 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 Cav3.2. 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 Cav3.2 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.
Footnotes
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This work was funded by an operating grant from the Canadian Institutes of Health Research and by faculty salary awards from the Alberta Heritage Foundation for Medical Research and the Canada Research Chair Program.
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Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
doi:10.1124/mol.109.059022.
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ABBREVIATIONS:
- CCR2
- chemokine (C-C motif) receptor 2
- MCP-1
- monocyte chemoattractant protein-1
- BMS CCR2 22
- 2-[(isopropylaminocarbonyl)amino]-N-[2-[[cis-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-(trifluoromethyl)benzamide
- RS102895
- 1′-[2-[4-(trifluoromethyl)phenyl]ethyl]-spiro[4H-3,1-be nzoxazine-4,4′-piperidin]-2(1H)-one
- RS504393
- 6-methyl-1′-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]-spiro[4H-3,1-benzoxazine-4,4′-piperidin]-2(1H)-one
- EYFP
- enhanced yellow fluorescent protein
- GDPβS
- guanosine 5′-[β-thio]diphosphate
- DTPA
- diethylenetriaminepentaacetic acid
- DRG
- dorsal root ganglion.
- Received June 30, 2009.
- Accepted October 28, 2009.
- Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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