Molecular mechanisms and functional consequences of P2X7 purinoceptor activation

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P2X7 is a nucleotide-gated ion channel that is prominently expressed by regulatory T cell subsets and plays an important role in inflammation. The primary goal of the proposed project is to elucidate the molecular mechanisms and functions of P2X7 ion channel gating on T cells. To this end, we have generated Nanobodies (single domain antibodies from immunized llamas) that effectively block or potentiate gating of P2X7 by extracellular nucleotides. These Nanobodies provide unique tools to assess the expression of P2X7 and to modulate the function of P2X7 on murine and human T cells during immune responses. Amino acid residues of P2X7 important for Nanobody binding and for gating of the receptor will be evaluated using P2X7 mutants and chimeras. A transgenic mouse model expressing a hyper-active P2X7-variant is expected to yield a better understanding of the role of P2X7 in physiological and pathological immune responses. Characterization of P2X7 expression and function in human T cells is expected to provide a basis for therapeutical applications of P2X7-specific Nanobodies. Long term goals of the project are to apply these Nanobodies for improved diagnostics and therapy of inflammatory diseases.