PT  - JOURNAL ARTICLE
AU  - Haitao You
AU  - Christophe Altier
AU  - Gerald W Zamponi
TI  - CCR2 receptor ligands inhibit Cav3.2 T-type calcium channels
AID  - 10.1124/mol.109.059022
DP  - 2009 Oct 28
TA  - Molecular Pharmacology
PG  - mol.109.059022
4099  - http://molpharm.aspetjournals.org/content/early/2009/10/28/mol.109.059022.short
4100  - http://molpharm.aspetjournals.org/content/early/2009/10/28/mol.109.059022.full
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 7 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 co-expressed 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 the case of N-type channels, this modulation does not require CCR2 receptor activation, and appears to involve a direct action of the ligand on the channel. Whole cell T-type calcium currents in acutely dissociated DRG 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 (DTPA), 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.The American Society for Pharmacology and Experimental Therapeutics