Cyclic nucleotides control a system which regulates Ca2+ sensitivity of platelet secretion

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Abstract
Cellular responses to extracellular signals are mediated by changes in the intracellular concentrations of one or more second messengers1. In platelets, inhibitory agonists increase intracellular cyclic-3′,5′-AMP ([cyclic AMP]i (refs 2, 3)) whereas excitatory agonists increase [Ca2+]i and/or [1,2-diacylglycerol]i (refs 4–9), and in some cases decrease [cyclic AMP]i (refs 10,11). Both activation and inhibition of platelet responses have been attributed to an increase in [cyclic-3′,5′-GMP]i (refs 8, 12). The activity of protein kinase C, which is associated with the platelet secretory response, is increased by both 1,2-diacylglycerol and Ca2+ (refs 4, 7, 8). The role of cyclic AMP may involve either inhibition of Ca2+ mobilization to the cytosol13 or stimulation of intracellular Ca2+ uptake14, and in addition inhibition of 1,2-diacylglycerol formation15,16. The relationship between cyclic-3′,5′-GMP (cyclic GMP) and other second messengers in platelet activation has not been defined. Using platelets made permeable by exposure to an intense electric field17,18, we demonstrate here modulation of the Ca2+sensitivity of platelet secretion by thrombin, and by 12-O-tetradecanoylphorbol-13-acetate (TPA) and l-oleyl-2-acetylglycerol (OAG), both potent activators of protein kinase C. The effect of thrombin is selectively modified by cyclic GMP and cyclic AMP. The response to OAG and TPA is also modulated by cyclic AMP but to a much lesser extent.