TAILIEUCHUNG - Báo cáo Y học: Irregular spiking in free calcium concentration in single, human platelets Regulation by modulation of the inositol trisphosphate receptors

Fluorescence ratio imaging indicates that immobilized, aspirin-treated platelets, loaded with Fura-2, respond to inositol 1,4,5-trisphosphate- (InsP3)-generating agonists such as thrombin by high-frequency, irregular rises in cytosolic [Ca 2+ ] i with spikes that vary in peak level and peak-to-peak interval. This differs from the regular [Ca 2+ ] i oscillations observed inother, larger cells. | Eur. J. Biochem. 269 1543-1552 2002 FEBS 2002 Irregular spiking in free calcium concentration in single human platelets Regulation by modulation of the inositol trisphosphate receptors Roosje M. A. van Gorp1 Marion A. H. Feijge1 Wim M. J. Vuist1 Martin B. Rook2 and Johan W. M. Heemskerk1 1 Departments of Biochemistry and Human Biology University of Maastricht the Netherlands department of Medical Physiology University Medical Centre Utrecht the Netherlands Fluorescence ratio imaging indicates that immobilized aspirin-treated platelets loaded with Fura-2 respond to inositol 1 4 5-trisphosphate- InsP3 -generating agonists such as thrombin by high-frequency irregular rises in cytosolic Ca2 i with spikes that vary in peak level and peak-to-peak interval. This differs from the regular Ca2 i oscillations observed in other larger cells. We found that the thiol-reactive compounds thimerosal 10 M and U73122 10 M evoked similar irregular Ca2 responses in platelets but in this case in the absence of InsP3 generation. Thrombin-induced spiking was acutely abolished by inhibiting phospholipase C or elevating intracellular cAMP levels while spiking with sulfhydryl reagents was only partially blocked by cAMP elevation. Confocal laser scanning microscopy using fluo-3-loaded platelets indicated that with all agonists or conditions the irregular spikes were almost instantaneously raised in various regions within a single platelet. When using saponin-permeabilized platelets we found that InsP3-induced Ca2 release from stores was stimulated by modest Ca2 concentrations pointing to a mechanism of InsP3-dependent Ca2 -induced Ca2 release CICR . This process was completely inhibitable by heparin. The Ca2 release by InsP3 but not the CICR sensor was negatively regulated by cAMP elevation. Thimerosal treatment did not release Ca2 from intracellular stores but markedly potentiated the stimulatory effect of InsP3. In contrast U73122 caused a heparin cAMP-insensitive Ca2 leak from stores that

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