Selective G Protein Coupling by C-C Chemokine Receptors

Abstract

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 beta2 in a pertussis toxin-sensitive manner, presumably through G beta gamma released from the Gi proteins. However, these three receptors demonstrated different specificity in coupling to the alpha subunits of the Gq class. While none of the receptors can couple to Galphaq/11, MCP-1Rb can couple to both Galpha14 and Galpha16, 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 Galpha14 but not to Galpha16, suggesting some of the C-C chemokine receptors, unlike the C-X-C chemokine receptors, discriminate against Galpha16, a hematopoietic-specific Galpha subunit. The intriguing specificity in coupling of the Gq 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 Gi-Gbetagamma-PLC beta2 pathway provides a potential target for developing broad spectrum anti-inflammatory drugs.

The chemokine CCL2 activates p38 mitogen-activated protein kinase pathway in cultured rat hippocampal cells

“…Chemokine receptors are linked to a number of downstream signal transduction pathways that mediate their biological effects (Bajetto et al, 2002). In immune cells, CCL2 signaling is reported to involve Gi/Go proteins and cellular calcium flux or activation of phospholipase C (Cambien et al, 2001;Dubois et al, 1996;Kuang et al, 1996). CCL2 has also been shown to trigger tyrosine phosphorylation and activation of Janus kinase 2 (JAK2)/ signal transducer and activator of transcription 3 (STAT3) pathway in immune cells (Mellado et al, 1998) and to activate mitogen-activated protein kinases (MAPK) (Dubois et al, 1996;Jimenez-Sainz et al, 2003).…”

Differential chemokine activation of CC chemokine receptor 1‐regulated pathways: ligand selective activation of Gα 14‐coupled pathways

“…CCR1 is thought to predominantly signal through G i/ocoupled pathways to regulate calcium flux and inhibit adenylyl cyclase [7]. CCR1 is unable to signal via G q/11 proteins but coupling to G 14 has been reported in transfected systems [8]. CCR1 is expressed in activated T cells, monocytes, eosinophils, dendritic cells and lymphocytes [9,10].…”

“…In this study we have pursued the idea that because of the co-expression of CCR1 with G § 14 and G § 16 and their likely ability to functionally couple to these signal transduction pathways [8], CCR1 agonists have differential abilities to activate different effectors.…”

Soluble Fractalkine Prevents Monocyte Chemoattractant Protein-1-Induced Monocyte Migration via Inhibition of Stress-Activated Protein Kinase 2/p38 and Matrix Metalloproteinase Activities

“…Many other activities have been ascribed to MCP-1, including induction of migration of memory/activated T cells (8), NK cells (9), and myeloid dendritic cells (10). MCP-1 mediates its cellular effects primarily through CCR2 receptors, triggering a complex array of signaling pathways including a pertussis toxin-sensitive rise of intracellular calcium (11), inhibition of adenyl cyclase (11), phospholipase C activation (12), stimulation of Src (13), Syk (13), Pyk2 (14), and Janus kinase 2 (15) tyrosine kinase activities as well as extracellular signal-regulated kinase (ERK) and stress-activated protein kinase (SAPK) activities (13,16,17).…”