CCR2 receptor ligands inhibit Cav3.2 T-type calcium channels.
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.
Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, T2N 4N1, Canada.
Haitao
H
You
Christophe
C
Altier
Gerald W
GW
Zamponi
D000818:Animals; D002121:Calcium Channel Blockers / Q000378:metabolism* / Q000494:pharmacology; D020864:Calcium Channels, N-Type / Q000096:biosynthesis / Q000378:metabolism; D020747:Calcium Channels, T-Type / Q000378:metabolism*; D002460:Cell Line; D018932:Chemokine CCL2 / Q000378:metabolism / Q000502:physiology; D006801:Humans; D008024:Ligands; D051381:Rats; D017207:Rats, Sprague-Dawley; D054390:Receptors, CCR2 / Q000378:metabolism*
C479952:CACNA1H protein, human; C111835:CCL2 protein, human; C509958:Cacna1h protein, rat; D002121:Calcium Channel Blockers; D020864:Calcium Channels, N-Type; D020747:Calcium Channels, T-Type; D018932:Chemokine CCL2; D008024:Ligands; D054390:Receptors, CCR2