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  • Title: Regulation of response to thromboxane A2 in CHRF-288 megakaryocytic cells.
    Author: Dorn GW.
    Journal: Am J Physiol; 1992 Apr; 262(4 Pt 1):C991-9. PubMed ID: 1533097.
    Abstract:
    Thromboxane A2 (TxA2) is a potent platelet aggregating agent and a necessary intermediate for platelet stimulation by several other platelet agonists. A potentially important means whereby platelet responses to TxA2 could be modified in vivo is regulation of TxA2 receptors and/or effectors by platelet precursor megakaryocytes. We therefore investigated the mechanisms that regulate the response to TxA2 in CHRF-288, a cultured cell line derived from megakaryocytes. Incubation of CHRF-288 with the TxA2 agonist U-44069 resulted in a biexponential 75% decrease in subsequent TxA2 receptor-stimulated, but not thrombin-stimulated, Ca2+ release (half times of 1 and 4.7 h) and a monoexponential 57% decline in TxA2 receptor agonist binding sites (half time of 4.6 h). Desensitization with U-44069 for 24 h increased the proportion of internal TxA2 receptors from 23 to 82% of total receptors. Inhibition of endocytosis with phenylarsine oxide prevented U-44069-induced receptor downregulation but only partially inhibited desensitization of the Ca2+ response, indicating that internalization of receptors is not an immediate requirement for desensitization but that receptor internalization and degradation are both necessary for maximal desensitization. In summary, CHRF-288 megakaryocytic cells desensitize to TxA2 through incomplete functional uncoupling of receptors from Ca2+ signal transducers and delayed downregulation of TxA2 receptors via accelerated receptor internalization and degradation.
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