Platelet metabolism and activation.

Stimulation and execution of platelet responses are intimately coupled to the cells' energy metabolism. The turnover of cytoplasmic ATP is higher than in most other cells; when it is lowered, platelet responses are powerfully inhibited. One-third of the total adenine nucleotides are present in the cytoplasm and a small fraction of these, 50% of the ADP, is bound to actin and not available to metabolism. These nucleotides are not synthesized de novo in platelets which readily form them from adenine, adenosine, and hypoxanthine. The remaining two-thirds are sequestered in the dense granules together with serotonin and divalent metal ions. NMR studies show that this ATP and ADP are stacked in large aggregates together with the divalent cations. Serotonin is incorporated into the aggregates by being positioned between, and in close proximity to, adjacent adenine rings. In the congenital platelet disorder, "Storage Pool Deficiency," the dense granule content is absent or markedly reduced, which may be caused by an impaired transport of ATP across the dense granule membrane. The content of the dense granules, the beta-thromboglobulin, albumin, fibrinogen, certain coagulation factors, fibronectin of the alpha-granules, and the acid hydrolases of the lysosomes are discharged by exocytosis, but the exact mechanisms are not known. This discharge, platelet secretion, is complete for the dense granule and alpha-granules contents, but is only 30% to 55% for the acid hydrolases. After pretreatment of platelets with certain amines, thrombin causes secretion of all beta-hexosaminidase, indicating that the beta-hexosaminidase usually retained during secretion is bound within the lysosomes at the acid pH but becomes dissociated by raising the pH with the amines. Agonist-induced platelet aggregation and secretion are accompanied by rapid changes in phosphoinositide metabolism which are usually monitored as the radioactivity in phospholipids of platelets preincubated with radioactive arachidonate, glycerol, inositol, or orthophosphate. The mechanisms for precursor incorporation are not well known and interpretations of published results are hampered by much uncertainty. Experimental support for the widely accepted coupling of receptor occupancy to the phosphodiesteratic hydrolysis of phosphatidylinositol or phosphatidylinositol-4,5-biphosphate is nonexistent. These two hydrolytic steps occur concomitantly and together with formation of diglyceride and phosphatidate; all four steps cannot be temporally resolved.(ABSTRACT TRUNCATED AT 400 WORDS)