CCR2 receptor ligands inhibit Cav3.2 T-type calcium channels

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dc.contributor.authorYou, Haitao
dc.contributor.authorAltier, Christophe
dc.contributor.authorZamponi, Gerald W.
dc.date.accessioned2018-05-28T16:49:14Z
dc.date.available2018-05-28T16:49:14Z
dc.date.issued2010-02-01
dc.description.abstractMonocyte 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.en_US
dc.identifier.citationYou, H., Altier, C., & Zamponi, G. W. (2010). CCR2 Receptor Ligands Inhibit Cav3.2 T-Type Calcium Channels. Molecular Pharmacology, 77(2), 211–217. https://doi.org/10.1124/mol.109.059022en_US
dc.identifier.doihttp://dx.doi.org/10.1124/mol.109.059022en_US
dc.identifier.urihttp://hdl.handle.net/1880/106690
dc.language.isoenen_US
dc.publisherThe American Society for Pharmacology and Experimental Therapeuticsen_US
dc.publisher.departmentPhysiology & Pharmacologyen_US
dc.publisher.facultyCumming School of Medicineen_US
dc.publisher.institutionUniversity of Calgaryen_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0en_US
dc.titleCCR2 receptor ligands inhibit Cav3.2 T-type calcium channelsen_US
dc.typeunknown
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