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Biophysical and Pharmacological Characterisations of Pannexin 1
[Thesis]. Manchester, UK: The University of Manchester; 2010.
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Abstract
The ATP-gated P2X7 receptors (P2X7Rs) play a key role in the release of pro-inflammatory cytokines in response to immunological challenges. Pannexin 1 (Panx1), conventionally described as a hemichannel forming protein, was suggested to be involved in the formation of the P2X7 large pore, which provides a conduit for large molecules such as fluorescent dyes. Firstly, this thesis demonstrated that the P2X7R-mediated dye uptake, a phenomenon attributed to the activation of Panx1, was suppressed by acidic pH and this inhibition was abolished in a P2X7 mutant (aspartic acid 197 to alanine) that was insensitive to extracellular pH. Then, the functional properties of human or mouse Panx1 in HEK293 cells were analysed in the absence of P2X7. The Panx1 currents were not affected by extracellular/intracellular calcium, but were reversibly inhibited by adenosine triphosphate (ATP) and non-specific anion channel blockers. Ion substitution experiments showed that Panx1 was permeable only to monovalent anions and single channel studies revealed a medium sized unitary conductance of Panx1 (~65 pS). Based on the evidence, this thesis concluded that Panx1 is an anion channel but not a hemichannel as originally proposed.