Response to elevated platelet cytosolic Ca ions (Homo sapiens)
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Description
Activation of phospholipase C enzymes results in the generation of second messengers of the phosphatidylinositol pathway. The events resulting from this pathway are a rise in intracellular calcium and activation of Protein Kinase C (PKC). Phospholipase C cleaves the phosphodiester bond in PIP2 to form 1,2 Diacylglycerol (DAG) and 1,4,5-inositol trisphosphate (IP3). IP3 opens Ca2+ channels in the platelet dense tubular system, raising intracellular Ca2+ levels. DAG is a second messenger that regulates a family of Ser/Thr kinases consisting of PKC isozymes (Nishizuka 1995). DAG achieves activation of PKC isozymes by increasing their affinity for phospholipid. Most PKC enzymes are also calcium-dependent, so their activation is in synergy with the rise in intracellular Ca2+. Platelets contain several PKC isoforms that can be activated by DAG and/or Ca2+ (Chang 1997).
Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=76005
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Saving...Bibliography
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History
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External references
DataNodes
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| Name | Type | Database reference | Comment |
|---|---|---|---|
| ABCC4 transported dense granule content | Metabolite | REACT_24476 (Reactome)  | |
| ABCC4 transported dense granule content | Metabolite | REACT_24718 (Reactome) | |
| ABCC4 | Protein | O15439 (Uniprot-TrEMBL) | |
| ADP | Metabolite | CHEBI:16761 (ChEBI) | |
| ATP | Metabolite | CHEBI:15422 (ChEBI) | |
| Activated conventional protein kinase C | Complex | REACT_4434 (Reactome) | |
| CALU | Protein | O43852 (Uniprot-TrEMBL) | |
| Ca2+ | Metabolite | CHEBI:29108 (ChEBI) | |
| DAG | CHEBI:17815 (ChEBI) | ||
| HSPA5 | Protein | P11021 (Uniprot-TrEMBL) | |
| PSAP | Protein | P07602 (Uniprot-TrEMBL) | |
| Phosphatidylserine | CHEBI:18303 (ChEBI) | ||
| Platelet alpha granule contents | Protein | REACT_21970 (Reactome) | |
| Platelet alpha granule contents | Protein | REACT_22076 (Reactome) | |
| Platelet alpha granule membrane components that are released on degranulation | Protein | REACT_25913 (Reactome) | |
| Platelet alpha granule membrane components that are released on degranulation | Protein | REACT_26523 (Reactome) | |
| Platelet dense granule content | REACT_21516 (Reactome) | ||
| Platelet dense granule content | Metabolite | REACT_21949 (Reactome) | |
| Platelet dense granule membrane components | Protein | REACT_21483 (Reactome) | |
| Platelet dense granule membrane components | Protein | REACT_22010 (Reactome) | |
| Platelet releasate | Protein | REACT_21475 (Reactome) | |
| Platelet releasate | Protein | REACT_21781 (Reactome) | |
| Platelet releasate cytosolic proteins | Protein | REACT_21985 (Reactome) | |
| Platelet releasate cytosolic proteins | Protein | REACT_21997 (Reactome) | |
| Platelet releasate secretory granule proteins | Protein | REACT_21832 (Reactome) | |
| Platelet releasate secretory granule proteins | Protein | REACT_21850 (Reactome) | |
| Protein Kinase C, conventional | Protein | REACT_4876 (Reactome) | These PKC isoforms are activated by PS in a Ca2+-dependent manner; they also bind DAG, which both increases the specificity of the enzyme for PS and also shifts the affinity for Ca2+ into the physiological range. They are targets of the tumour-promoting phorbol ester PMA, which activates these enzymes by eliminating the requirement for DAG and decreasing the concentration of Ca2+ needed for activation. |
| STX4 | Protein | Q12846 (Uniprot-TrEMBL) | |
| STXBP3 | Protein | O00186 (Uniprot-TrEMBL) | |
| p-STXBP3 | Protein | O00186 (Uniprot-TrEMBL) |
Annotated Interactions
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| Source | Target | Type | Database reference | Comment |
|---|---|---|---|---|
| ABCC4 | mim-catalysis | REACT_23865 (Reactome) | ||
| ADP | Arrow | REACT_1045 (Reactome) | ||
| ADP | Arrow | REACT_133 (Reactome) | ||
| ATP | REACT_1045 (Reactome) | |||
| ATP | REACT_133 (Reactome) | |||
| Activated conventional protein kinase C | mim-catalysis | REACT_1045 (Reactome) | ||
| Activated conventional protein kinase C | mim-catalysis | REACT_133 (Reactome) | ||
| Ca2+ | REACT_286 (Reactome) | |||
| DAG | Arrow | REACT_286 (Reactome) | ||
| DAG | REACT_286 (Reactome) | |||
| Phosphatidylserine | REACT_286 (Reactome) | |||
| Protein Kinase C, conventional | REACT_286 (Reactome) | |||
| REACT_1045 (Reactome) | At the beginning of this reaction, 1 molecule of 'ATP', and 1 molecule of 'Syntaxin 4' are present. At the end of this reaction, 1 molecule of 'Phosphorylated syntaxin 4', and 1 molecule of 'ADP' are present. This reaction is mediated by the 'calcium-dependent protein kinase C activity' of 'Activated Ca++ and DAG dependent PKC'. | |||
| REACT_133 (Reactome) | At the beginning of this reaction, 1 molecule of 'ATP', and 1 molecule of 'Platelet SEC1 protein' are present. At the end of this reaction, 1 molecule of 'Phosphorylated platelet SEC1 protein', and 1 molecule of 'ADP' are present. This reaction is mediated by the 'calcium-dependent protein kinase C activity' of 'Activated Ca++ and DAG dependent PKC'. | |||
| REACT_13534 (Reactome) | After Platelet activation 'Proactivator polypeptide' from the lysosomal lumen is released in to the extracellular platelet releasate. | |||
| REACT_13546 (Reactome) | After Platelet activation '78 kDa glucose-regulated protein' from the endoplasmic reticulum lumen is released in to the extracellular platelet releasate. | |||
| REACT_13580 (Reactome) | After Platelet activation 'Calumenin' from the endoplasmic reticulum lumen is released in to the extracellular platelet releasate. | |||
| REACT_21266 (Reactome) | Constituents of the platelet dense granule membrane are incorporated into the platelet membrane following exocytosis of granule content. | |||
| REACT_21290 (Reactome) | Platelet releasate contains a range of proteins that do not originate in specialized storage granules. In some cases platelet lysis may contribute to the presence of these proteins in the platelet relesate. | |||
| REACT_21324 (Reactome) | Platelet releasate contains a range of proteins that do not originate in specialized storage granules. In some cases platelet lysis may contribute to the presence of these proteins in the platelet relesate. | |||
| REACT_21347 (Reactome) | Platelet releasate contains a range of proteins that do not originate in specialized storage granules. In some cases platelet lysis may contribute to the presence of these proteins in the platelet relesate. | |||
| REACT_21351 (Reactome) | Alpha granules contain mainly polypeptides such as fibrinogen, von Willebrand factor, growth factors and protease inhibitors that supplement thrombin generation at the site of injury. In addtion to their role in hemostasis, platelets also contain angiogenesis stimulators and inhibitors (Italiano et al. 2008). | |||
| REACT_21354 (Reactome) | ADP is the most important constituent of dense granules, essential for recruiting platelets to the site of vascular injury. Other components include ATP, Ca++, GDP, GTP, Mg++, orthophospate, pyrophosphate, and serotonin. | |||
| REACT_21394 (Reactome) | Constituents of the platelet alpha granule membrane are incorporated into the platelet membrane following exocytosis of granule content. | |||
| REACT_23865 (Reactome) | ABCC4 (Multidrug resistance protein 4 /MOAT-B) is a member of the MRP/ABCC subfamily of ATP-binding cassette transporters, capable of pumping a wide variety of endogenous and xenobiotic anionic compounds out of the cell. ABCC4 also transports molecules involved in cellular signalling, including cyclic nucleotides, eicosanoids, urate and conjugated steroids. ABCC4 has a dual localisation in polarised cells that suggests a key function in cellular protection and extracellular signalling pathways. It is also highly expressed on platelet dense granule membranes where it is believed to contribute to the accumulation of dense granule content. | |||
| REACT_286 (Reactome) | The conventional Protein Kinase C (cPKC) isoforms have two membrane-targetting domains, a C1 domain which binds to the membrane lipid diacylglycerol (DAG) and a C2 domain which binds membrane phospholipids such as phosphatidylserine, in a calcium-dependent manner. Association of both domains with the plasma membrane produces a conformational change that releases an autoinhibitory pseudosubstrate segment from the substrate-binding cavity, allowing substrate binding and downstream signaling. | |||
| STX4 | Arrow | REACT_1045 (Reactome) | ||
| STX4 | REACT_1045 (Reactome) | |||
| STXBP3 | REACT_133 (Reactome) | |||
| p-STXBP3 | Arrow | REACT_133 (Reactome) |
