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Role of the purine nucleotide messengers cyclic ADP-ribose and ADP-ribose in T-lymphocyte biology

Subject Area Pharmacology
Term from 2009 to 2014
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 86975855
 
P2X7 and TRPM2 are cation channels expressed by T lymphocytes that are gated by extra- and intracellular adenine nucleotides, respectively. P2X7, in addition, mediates membrane permeability changes towards multiple substrates including nucleotides and drugs. Although increasing evidence points to a pivotal role of both channels in inflammation, their effects on T cells remain unclear. The primary goal of the current project is thus to characterize the roles of P2X7 and TRPM2 during the early events of T cell activation. To this end, we will use live cell Ca2+ and ATP imaging, HPLC, and patch-clamp techniques to study the roles of these channels in TCR signaling. Especially, we will test the hypothesis that 2`-deoxy-adenosine diphosphoribose (2´-deoxy-ADPR), instead of ADPR, is the major endogenous activating ligand of TRPM2, and characterize P2X7-induced changes in T cell permeability to nucleotides and other signaling molecules, thereby providing a link between the worlds of signaling by intra- and extracellular nucleotides. Characterization of the roles of P2X7 and TRPM2 in TCR signaling will provide the basis for assessing the potential of new therapeutic strategies aimed at targeting these two ion channels.
DFG Programme Research Grants
Participating Person Dr. Ralf Fliegert
 
 

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