Protein kinase C-dependent desensitization of HDL3-activated phospholipase C in human platelets.
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Abstract
In isolated human platelets, exposure of subfraction 3 high-density lipoprotein (HDL3) binding sites to high concentrations of HDL3 (1 mg/mL) causes rapid desensitization of HDL3 (50 micrograms/mL)-stimulated breakdown of phosphatidylcholine, as shown in approximately a 70% depression of the maximal 1,2-diacylglycerol release activity by phospholipase C. This desensitization is HDL3 dose dependent (IC50, 150 +/- 20 micrograms/mL, n = 6) and time dependent (t1/2, < 30 seconds). It requires the binding of HDL3, as pretreatment of HDL3 by tetranitromethane does not cause the desensitization of HDL3-induced phospholipase C activity. Permeabilization of human platelets with 10 micrograms/mL digitonin, used to permit access of charged inhibitors to the cytosol, does not interfere with the pattern of HDL3 (1 mg/mL)-induced desensitization of HDL3 (50 micrograms/mL)-stimulated phospholipase C. Inhibitors of protein kinase C (100 mumol/L H-7 and 10 mumol/L staurosporine) markedly inhibit desensitization of HDL3-induced phospholipase C activity, whereas cAMP-dependent protein kinase inhibitor (1 mumol/L), heparin (100 nmol/L), or concanavalin A (0.25 mg/mL) were ineffective. HDL3-induced desensitization is accompanied at least by the phosphorylation of the 94- and 110-kD proteins. Inhibition of HDL3-induced desensitization by 100 mumol/L H-7 or 10 mumol/L staurosporine is characterized by a marked reduction of the phosphorylation state of these proteins in permeabilized platelets. Whereas protein kinase C inhibitors fully inhibited the phosphorylation of the 94- and 110-kD proteins, inhibitors of protein kinase A were less effective. These data establish that phosphorylation by protein kinase C represent a step in the desensitization of HDL3 binding sites in human platelets.
- Copyright © 1994 by American Heart Association
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- Protein kinase C-dependent desensitization of HDL3-activated phospholipase C in human platelets.H Nazih, F Nazih-Sanderson, V Magret, B Caron, J Goudemand, J C Fruchart and C DelbartArteriosclerosis, Thrombosis, and Vascular Biology. 1994;14:1321-1326, originally published August 1, 1994https://doi.org/10.1161/01.ATV.14.8.1321
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- Protein kinase C-dependent desensitization of HDL3-activated phospholipase C in human platelets.H Nazih, F Nazih-Sanderson, V Magret, B Caron, J Goudemand, J C Fruchart and C DelbartArteriosclerosis, Thrombosis, and Vascular Biology. 1994;14:1321-1326, originally published August 1, 1994https://doi.org/10.1161/01.ATV.14.8.1321