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Regulation of Calcium in Macrophages

The dual ligand screen in RAW cells, conducted by the AfCS during the initial 5 year funding period, identified frequent synergies between ligands, indicating interactions between signaling networks. In recent months, the AfCS laboratories collaborated to define the pathways that lead to synergy in the calcium response to two ligands, C5a and UDP, and to test a signaling model that can be interrogated and validated or altered. This effort has been undertaken as a prototype for approaches to understanding cell signaling. C5a activates cell signaling through the Gαi-linked C5a receptor, while UDP signals through Gαq-linked PY2 receptors. Synergies between these pathways have been observed in other cell types, but the mechanisms of synergy are not known, and the functional effects on macrophages have not been defined. Two additional ligands, LPA and PAF robustly stimulate the release of intracellular calcium but with different unique response patterns and differential synergy with C5a. These ligands were all chosen for study both as a general probe into pathways for signaling by G-protein coupled receptors and because of the important role of C5a in inflammation.

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