Calcium and Chemotaxis

Abstract

Chemokines are chemoattractant cytokines that act through G protein-coupled receptors (GPCRs) to mediate the directed migration (or chemotaxis) of leukocytes. Chemokine receptors couple to heterotrimeric guanine nucleotide-binding proteins (G proteins) to activate phosphoinositide 3-kinase (PI3K) and phospholipase C (PLC). PI3K phosphorylates phosphatidylinositol 4,5-bisphosphate (PIP 2 ) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP 3 ), which is critical for leukocyte chemotaxis. PLC-β hydrolyzes PIP 2 to produce both inositol 1,4,5-trisphosphate (IP 3 ), which stimulates intracellular Ca 2+ mobilization, and diacylglycerol (DAG), which is required for the activity of many isoforms of protein kinase C (PKC). PLC-β2 and PLC-β3 are not required for the chemotaxis of neutrophils; however, the role of these enzymes in mediating lymphocyte chemotaxis has been unclear. Bach et al . isolated T lymphocytes from wild-type mice and mice deficient in both PLC-β2 and PLC-β3 (PLC-β2β3 KO mice) and performed chemotaxis assays in which they determined the percentages of cells that migrated in response to the chemokine SDF-1α, the ligand for the chemokine receptor CXCR4. The percentage of responding PLC-β2β3 KO T lymphocytes was about half that of the wild-type cells, over a range of concentrations of SDF-1α. This was not due to differences in CXCR4 abundance between the PLC-β2β3 KO and wild-type T lymphocytes, as assessed by flow cytometry. Chelation of intracellular Ca 2+ largely inhibited chemotaxis of wild-type T lymphocytes to SDF-1α, whereas pharmacological inhibition of PKC had no such effect. Intracellular Ca 2+ flux assays demonstrated that SDF-1α-induced Ca 2+ mobilization was severely compromised in PLC-β2β3 KO compared with wild-type T lymphocytes. These data suggest that PLC-β-mediated intracellular Ca 2+ mobilization, but not PKC activation, is important for T lymphocyte chemotaxis. Although chemokine receptor-mediated activation of PI3K is critical for the chemotaxis of all leukocyte subsets, the contribution of PLC-β isoforms to chemotaxis appears to be cell-specific. T. L. Bach, Q.-M. Chen, W. T. Kerr, Y. Wang, L. Lian, J. K. Choi, D. Wu, M. G. Kazanietz, G. A. Koretzky, S. Zigmond, C. S. Abrams, Phospholipase Cβ is critical for T cell chemotaxis. J. Immunol. 179 , 2223-2227 (2007). [PubMed]