SELECTIVE G-PROTEIN COUPLING BY C-C CHEMOKINE RECEPTORS

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 i n 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-induc ed accumulation of inositol phosphates with PLC beta 2 in a pertussis toxin-sensitive manner, presumably through G beta gamma released from the G(i) proteins. However, these three receptors demonstrated differe nt specificity in coupling to the alpha subunits of the G(q) class. Wh ile none of the receptors can couple to G alpha q/11, MCP-1Rb can coup le to both G alpha 14 and G alpha 16, but its splicing variant, MCP-1R b, cannot. Since MCP-1Ra and -b differ only in their C-terminal intrac ellular domains, the C-terminal ends of MCP-1Rs determine G protein co upling specificity. CKR-1 can couple to G alpha 14 but not to G alpha 16, suggesting some of the C-C chemokine receptors, unlike the C-X-C c hemokine receptors, discriminate against G alpha 16, a hematopoietic-s pecific G alpha subunit. The intriguing specificity in coupling of the G(q) class of G proteins implies that the chemokines may be involved in some distinct functions in vivo. The commonality of the chemokine r eceptors in coupling to the G(i)-G beta gamma-PLC beta 2 pathway provi des a potential target for developing broad spectrum anti-inflammatory drugs.