cAMP reduces the affinity of Ca²⁺‐triggered secretion in platelets

Abstract

Prostacyclin and other related compounds known to increase intracellular cAMP levels inhibit platelet responses. The mechanisms involved are only partially known, especially those concerning the complex relations between Ca 2 ÷ and cAMP as opposite intracellular mediators. Here, we have investigated aggregation and secretion in quin2-1oaded platelets under conditions in which Ca 2 ÷ and cAMP are the only intracellular mediators. Our results show that cAMP inhibits aggregation and secretion in ionophore-treated cell without modifying their intracellular Ca 2 + levels. This result suggests that the inhibition takes place on some intracellular target for Ca 2 +. cyclic AMP; Ionomycin; Secretion; Piatelet; intracellular Ca 2 +

Prostacyclin inhibits platelet aggregation induced by phorbol ester or Ca2+ ionophore at steps distal to activation of protein kinase C and Ca2+-dependent protein kinases

“…The Ca2+-dependent phosphorylation of the 20 and 47 kDa proteins induced by ionophore A23187 was not inhibited by PGI2. In agreement with previous studies [10,33,34], aggregation but not shape change was inhibited by PGI2. Since Ca2+ mobilization induced by ionophore A23187 was not inhibited by PGI2 (see also refs.…”

“…Since Ca2+ mobilization induced by ionophore A23187 was not inhibited by PGI2 (see also refs. [33,34]), these results indicate that aggregation is inhibited by PGI2 at steps distal to Ca2+-dependent phosphorylation of 20 and 47 kDa proteins. This result is somewhat unexpected: biochemical studies using purified proteins have demonstrated that protein kinase A phosphorylates MLCK, thereby diminishing its enzymic activity and decreasing its affinity for calmodulin [4,37].…”

“…Different studies, however, have indicated that other target sites exist for cyclic AMP. For example, cyclic AMP inhibits Ca2+-dependent secretion and aggregation at steps distal to Ca2l mobilization [33][34][35][36]. Also, it has been reported that the catalytic subunit of cyclic AMPdependent kinase phosphorylates the purified Ca2"/ calmodulin-dependent MLCK, thereby decreasing its ability to phosphorylate myosin light chain [37].…”

Baicalein inhibits agonist- and tumor cell-induced platelet aggregation while suppressing pulmonary tumor metastasis via cAMP-mediated VASP phosphorylation along with impaired MAPKs and PI3K-Akt activation

“…For this, cAMP activates a protein kinase that phosphorylates an ATP-dependent calcium-pump. Subsequently, Ca 2+ uptake into the dense tubular system is subsequently decreased, resulting in the inhibition of platelet activation cascades [83][84][85]. In the present study, we found that treatment with baicalein elevated the level of cAMP in resting platelets.…”

Functional relationship between cyclic AMP-dependent protein phosphorylation and platelet inhibition

“…Other studies discovered additional target sites for platelet inhibition by cyclic AMP. For example, several investigators reported that cyclic AMP inhibits secretion and aggregation induced by Ca2+ ionophore at steps distal to Ca2l mobilization [6][7][8][9]. Also, modest increments in platelet cyclic AMP were reported to abolish platelet-activatingfactor-induced aggregation and secretion, whereas they had little effect on phosphoinositide hydrolysis and elevation of cytosolic Ca2+ concentration induced by platelet-activating factor [10].…”