PubMed · 4571866
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G Tisman. 1973. Constipated lymphocytes.. https://doi.org/10.7326/0003-4819-78-3-453
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Pathological conditions such as coronary artery disease are clinically controlled via therapeutic regulation of platelet activity. Thrombin, through protease-activated receptor (PAR) 1 and PAR4, plays a central role in regulation of human platelet function in that it is known to be the most potent activator of human platelets. Currently, direct thrombin inhibitors used to block platelet activation result in unwanted side effects of excessive bleeding. An alternative therapeutic strategy would be to inhibit PAR-mediated intracellular platelet signaling pathways. To elucidate the best target, we are studying differences between the two platelet thrombin receptors, PAR1 and PAR4, in mediating thrombin's action. In this study, we show that platelet activation by PAR1-activating peptide (PAR1-AP) requires a phospholipase D (PLD)-mediated phosphatidic acid (PA) signaling pathway. We show that this PAR1-specific PA-mediated effect is not regulated through differential granule secretion after PAR-induced platelet activation. Perturbation of this signaling pathway via inhibition of lipid phosphate phosphatase-1 (LPP-1) by propranolol or inhibition of the phosphatidylcholine-derived phosphatidic acid (PA) formation by PLD with a primary alcohol significantly attenuated platelet activation by PAR1-AP. Platelet activation by thrombin or PAR4-AP was insensitive to these inhibitors. Furthermore, these inhibitors significantly attenuated activation of Rap1 after stimulation by PAR1-AP but not thrombin or PAR4-AP. Because PA metabolites such as diacylglycerol play an important role in intracellular signaling, identifying crucial differences in PA regulation of PAR-induced platelet activation may lead to a greater understanding of the role of PAR1 versus PAR4 in progression of thrombosis.
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The powerful combination of subcellular fractionation and protein identification by electrospray ionization tandem mass spectrometry (ESI-MS/MS) pioneered the molecular elucidation of neuromelanin (NM) granules. We recently isolated NM granules from the human brain and succeeded in the establishment of the first protein profile of this compartment. NM granules are pigmented organelles, which are mainly found in the catecholaminergic neurons of the human substantia nigra (SN) pars compacta and the locus coeruleus. These granules contain the insoluble pigment NM, which is regarded as the most important iron storage system in these neurons. A global examination of NM granules, however, has so far been hampered due to the lack of a pigmented brain stem in rodents, the absence of an appropriate experimental system and their scarcity in the human brain. 'Subcellular proteomics', which increasingly emerges as the method of choice to characterize cellular compartments and to elucidate their biogenesis, has recently been shown to be an adequate approach to tackle a thorough description of NM granules. Thereby, NM granules could be described as a 'lysosome-related organelle'. This indicates a genetic program underlying a biogenesis of NM rather than its autoxidative formation.