Chemokines are a large family of low-molecular weight cytokines, which regulate the chemotaxis of leucocytes and play an important role in immunological processes. Chemokine receptors utilize G Proteins for signaling. One remarkable feature in the chemokine field is the redundancy and promiscuity of both chemokines and chemokine receptors. Forty-five chemokines and eighteen chemokine receptors have been indentified to date. Most of the chemokine receptors can recognize multiple chemokines, and many chemokines are shared by several chemokine receptors. Chemokine receptors are typically coupled to G_i proteins, however, it remains unclear whether the chemokine receptors can interact with other G proteins. The extent by which different chemokines regulate G protein functions through a singl...[ Read more ]

Chemokines are a large family of low-molecular weight cytokines, which regulate the chemotaxis of leucocytes and play an important role in immunological processes. Chemokine receptors utilize G Proteins for signaling. One remarkable feature in the chemokine field is the redundancy and promiscuity of both chemokines and chemokine receptors. Forty-five chemokines and eighteen chemokine receptors have been indentified to date. Most of the chemokine receptors can recognize multiple chemokines, and many chemokines are shared by several chemokine receptors. Chemokine receptors are typically coupled to G_i proteins, however, it remains unclear whether the chemokine receptors can interact with other G proteins. The extent by which different chemokines regulate G protein functions through a single chemokine receptor is also unclear. Hence, the interactions of six chemokine receptors CCR1, CCR2a, CCR2b, CCR3, CCR5 and CCR7 with G₁₄ and G₁₆ were studied in cotransfection systems. Results revealed that three of them, CCR1, CCR2b and CCR3 were coupled to both G₁₄ and G₁₆, while others could not. The potencies for five ligands of CCR1 (LKN-1, MIP-1α, RANTES, MCP-3 and MIP-1δ) to induce G₁₄ and G₁₆-mediated responses were then examined. Results showed that chemokines can differentially induce stimulation of phospholipase C via G₁₄ and G₁₆. Moreover, different chemokines differentially induced phosphorylation of the extracellular signal-regulated kinase ( ERK ) . ERK responses appeared to be regulated by both G₁₄ and G_i proteins. Lastly, the possibility of CCR1 to signal through Gα₁₄ and Gα₁₆ was investigated in THP-1 and U-937 cells, which possess endogenous CCR1, Gα₁₄ and Gα₁₆. In these cells, CCR1 did not appear to mediate intracellular calcium release interact via Gα₁₄ and Gα₁₆. In summary, multiple chemokines may differentially regulate receptor-mediated signaling pathways and their receptors possess the ability to propagate the signals via G proteins other than those of the G_i family, although chemokine receptors might prefer to utilize G_i proteins in certain physiological systems.