Chemokine receptor homo- or heterodimerization activates distinct signaling pathways

Chemokine receptors of both the CC and CXC families have been demonstrated to undergo a ligand-mediated homodimerization process required for Ca2+ flu x and chemotaxis. We show that, in the chemokine response, heterodimerizati on is also permitted between given receptor pairs, specifically between CCR 2 and CCR5, This has functional consequences, as the CCR2 and CCR5 ligands monocyte chemotactic protein-1 (MCP-1) and RANTES (regulated upon activatio n, normal T cen-expressed and Secreted) cooperate to trigger calcium respon ses at concentrations 10- to 100-fold lower than the threshold for either c hemokine alone. Heterodimerization results in recruitment of each receptor- associated signaling complex, but also recruits dissimilar signaling pathwa ys such as G(q/11) association, and delays activation of phosphatidyl inosi tol 3-kinase, The consequences are a pertussis toxin-resistant Ca2+ flux an d triggering of cell adhesion rather than chemotaxis, These results show th e effect of heterodimer formation on increasing the sensitivity and dynamic range of the chemokine response, and may aid in understanding the dynamics of leukocytes at limiting chemokine concentrations in vivo.