Langley, David Brian; (1995) Purinoceptors and the control of eicosanoid release from cultured rat astrocytes. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

CNS astrocytes in culture are known to be capable of synthesising and releasing a variety of eicosanoids. However, we are far from understanding both the identity of the signal molecules which elicit this response and the intracellular pathways which regulate it. ATP is one of the very few biologically relevant signals known to promote eicosanoid release from cultured astrocytes. A range of purine and pyrimidine nucleotides were examined for their ability to promote eicosanoid release from astrocytes. In terms of TXA2 release, the specific P2Y purinoceptor agonist 2- MeSATP was found to be the most potent agent examined, with ATP, ADP, UTP and UDP all having similar potencies. UTP and UDP were found to be more effective than ATP or other nucleotides in their ability to promote TXA2 release. A range of other nucleotide di- and triphosphates also elicited TXA2 release from astrocytes. The effect of the removal from cultures of microglia and serum depletion was investigated, and both these regimens were found to reduce TXA2 release for all nucleotides tested. A range of nucleotides were found to be able to evoke changes in [Ca2+]i and stimulate the production of inositol phosphates. The reason why agents such as noradrenaline (NA) fail to evoke eicosanoid release from astrocytes was examined. An increase in [Ca2+]i is essential for eicosanoid release, however, no differences in the Ca2+ transients evoked by ATP or NA were detected. NA was found to inhibit the ability of a range of nucleotides to stimulate TXA2 release from these cells. Astrocytes were previously thought to possess only IP3-sensitive Ca2+ pools, however, the presence of IP3-insensitive ryanodine receptors was detected, but these are not involved in TXA2 release. These results may have significance in terms of P2 purinoceptor classification and astrocyte function within the CNS.

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