Platelet activation inositol trisphosphates

Phospholipase C (both p and y) catalyzes the hydrolysis of Phosphatidyl inositol bisphosphate (PIPj) leading to the generation of diacylglycerol (DAG) and inositol trisphosphate (IP,). In platelets, thrombin and thromboxane-A, (TxA,) stimulate PLC-p. PLC-P has three isotypes. It is known that PLC-pi and PLC-P3 are activated by G-protein... 

Fig. 5.4 Interactions among dynorphin, gluteimate, and Idnin receptors in spinal cord injury. Dinorphin (D) glutamate (Glu) arginine (Arg) nitric oxide synthase (NOS) nitric oxide (NO) superoxide (O2 ) peroxynitrite (ONOO ) phosphatidylcholine (PtdCho) cytosolic phosphoUpase A2 (CPLA2) arachidonic acid (ARA) phospholipase C (PLC) diacylglycerol (DAG) inositol 1,4,5-trisphosphate (InPs) endoplasmic reticulum (ER) platelet-activating factor (RAF) reactive oxygen species (ROS) and 4-hydroxynonenal (4-HNE)...

Connolly, T., Laiving, W. and Majerus, P. (1986). Protein kinase C phosphorylates human platelet inositol trisphosphate 5 -phosphomonesterase increasing the phosphatase activity. Cell 46, 951-958... 

In platelets, protein kinase C activates the enzyme inositol l,4,5-trisphosphate-5-phosphomonoesterase, which breaks down inositol 1,4,5-trisphosphate (IP3) to inositol 1,4-bisphosphate (IP2). What effect would this have on Ca2+ release due to receptors that stimulate phospholipase C ... 

Stimulation of platelets also leads to the fonnation of polyphosphoinositides that are phosphorylated in the 3-position on the inositol ring, especially PI 3-phosphate, PI 3,4-bisphosphate and PI 3,4,5-trisphosphate (Kucera and Rittenhouse, 1990), due to a PI 3-kinase that becomes activated upon receptor stimulation. The 3-phosphoiylated pho hoinositides are not hydrolyzed by PPI-PLC and are probably not taldng part in the PPI-metaboIism. It has been postulated that they contribute to the actin polymerization that takes place upon platelet stimulation (Downes and Carter, 1991). 

If one role of PKG is to decrease smooth muscle intracellular Ca levels, then the mechanism by which this occurs is still not completely defined. Several protein substrates that are known to be phosphorylated by activation of PKG have been identified in SMCs, platelets, and other tissues. Interestingly, some of these proteins have been shown by others to regulate intracellular Ca levels in various cell types. For example, phospholamban, when phosphorylated by PKA in cardiac myocytes, dissociates from sarcoplasmic reticulum (SR) Ca -ATPase resulting in the enhanced sequestration of Ca into the SR (Lindemann et al., 1983). A similar effect of PKG activation has been shown in SMCs (Cornwell et al., 1991 Karczewski et al., 1992 Raeymaekers et al., 1988 Sarcevic et al., 1989). Using another example, Supattopone et al. (1988) reported that PKA-dependent phosphorylation of the inositol 1,4,5-trisphosphate (IP3) receptor in broken-cell fractions decreased Ca release from brain microsomes. Our laboratory has recently shown that the IP3 receptor is also phosphorylated by PKG in vitro on the major PKA phosphorylation site (i.e., Ser-1755) (Komalavilas and Lincoln,... 

It has been indicated that the phosphodiesteratic cleavage of the Inositol phospholipids (phospholipase C activity) precedes and might trigger the activation of phospholipase A2 in stimulated platelets.1l >20,21 It seems that some of the products formed during the phosphodiesteratic cleavage of the inosltides could be related to Ca2+ mobilization. One of these products, myoinositol 1,4,5-trisphosphate. 

GU-7, a 3-arylcoumarin derivative, has been isolated fi om Glycyrrhizae radix, which is a crude herbal medicine. GU-7 caused inhibition of platelet aggregation, phosphorylation of 40K and 20K dalton proteins, inositol 1,4,5-trisphosphate production, intraplatelet calcium increase and phosphodiesterase activity in vitro. The data indicate that GU-7 inhibits platelet aggregation by increasing intraplatelet cAMP concentration. Antiplatelet action may also explain the mechanism by which traditional medicines are effective in diabetic neuropathy [236]. Osthole causes hypotension in vivo, and inhibits platelet aggregation and smooth muscle contraction in vitro. It may interfere with calcium influx and cyclic nucleotide phosphodiesterases [12]. Cloricromene, a synthetic coumarin derivative, also possesses antithrombotic-antiplatelet activity [237]. Some of these properties of cloricromene have been attributed to the inhibition of arachidonate release from membrane phospholipids [12]. 

Qi R, Liao F, Inoue K, Yatomi Y, Sato K, Ozaki Y (2000) Inhibition by diallyl trisulfide, a garlic component, of intracellular Ca mobilization without affecting inositol-1,4,5-trisphosphate (IP3) formation in activated platelets. Biochem Pharmacol 60(10) 1475-1483. doi 10.1016/s0006-2952(00)00467-6... 

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