The C-C chemokines are major mediators of chemotaxis of monocytes and some T cells in inflammatory reactions. The pathways by which the C-C chemokine receptors activate phospholipase C (PLC) were investigated in cotransfected COS-7 cells. The C-C chemokine receptor-1 (CKR-1), the MCP-1 receptor-A (MCP-1Ra), and MCP-1Rb can reconstitute ligand-induced accumulation of inositol phosphates with PLC 2 in a pertussis toxin-sensitive manner, presumably through G released from the G proteins. However, these three receptors demonstrated different specificity in coupling to the subunits of the G class. While none of the receptors can couple to Gq/11, MCP-1Rb can couple to both G14 and G16, but its splicing variant, MCP-1Rb, cannot. Since MCP-1Ra and -b differ only in their C-terminal intracellular domains, the C-terminal ends of MCP-1Rs determine G protein coupling specificity. CKR-1 can couple to G14 but not to G16, suggesting some of the C-C chemokine receptors, unlike the C-X-C chemokine receptors, discriminate against G16, a hematopoietic-specific G subunit. The intriguing specificity in coupling of the G class of G proteins implies that the chemokines may be involved in some distinct functions in vivo. The commonality of the chemokine receptors in coupling to the G-G-PLC 2 pathway provides a potential target for developing broad spectrum anti-inflammatory drugs.

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