Generation of transgenic mice to investigate the expression patterns, protein interactions and physiological functions of P2X4, P2X6 and P2X7 receptors

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P2X receptors (P2XRs) are ATP-activated Ca2+-permeable cation channels that have been shown to influence a variety of cell functions. Usually more than one of the seven known P2X subunits (P2X1-P2X7) are expressed in a given tissue or cell type. The functional characterization of P2XRs in native tissues has been hampered by the rapid catabolism of the agonist, the simultaneous activation of different P2XR subtypes and metabotropic P2Y receptors as well as the lack of subtype-specific ligands. Therefore, the in vivo functions of P2XRs are largely unknown. Deletion of single P2X genes in mice revealed the involvement of P2XRs in such diverse physiological processes as osteogenesis, interleukine production, micturition, pain transmission and reproduction. Despite the wide-spread expression of P2XRs in brain, no effects on motor function or behavior have been identified so far in the available knockout animals. However, electrophysiological studies indicate an important role of P2XRs in the modulation of synaptic transmission and the development of neuropathic pain. In this project, we propose to generate transgenic mice that over-express epitope-tagged and dominant-negative P2X subunits under their endogenous promoters to investigate the expression patterns, functions and protein interactions of P2X4, P2X6 and P2X7 subunits in glia cells and neurons of the mammalian central nervous system.