Platelet homeostasis (Homo sapiens)
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Description
Under normal conditions the vascular endothelium supports vasodilation, inhibits platelet adhesion and activation, suppresses coagulation, enhances fibrin cleavage and is anti-inflammatory in character. Under acute vascular trauma, vasoconstrictor mechanisms predominate and the endothelium becomes prothrombotic, procoagulatory and proinflammatory in nature. This is achieved by a reduction of endothelial dilating agents: adenosine, NO and prostacyclin; and by the direct action of ADP, serotonin and thromboxane on vascular smooth muscle cells to elicit their contraction (Becker et al. 2000).
Cyclooxygenase-2 (COX-2) and endothelial nitric oxide synthase (eNOS) are primarily expressed in endothelial cells. Both are important regulators of vascular function. Under normal conditions, laminar flow induces vascular endothelial COX-2 expression and synthesis of Prostacyclin (PGI2) which in turn stimulates endothelial Nitric Oxide Synthase (eNOS) activity. PGI2 and NO both oppose platelet activation and aggregation, as does the CD39 ecto-ADPase, which decreases platelet activation and recruitment by metabolizing platelet-released ADP. Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=418346
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History
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External references
DataNodes
| View all... |
| Name | Type | Database reference | Comment |
|---|---|---|---|
| ADP | Metabolite | CHEBI:16761 (ChEBI)  | |
| APOB(28-4563)
[extracellular region] | Protein | P04114 (Uniprot-TrEMBL) | |
| ATP [plasma membrane] | Metabolite | CHEBI:15422 (ChEBI) | |
| ATP2A1-3 | Protein | REACT_24286 (Reactome) | |
| ATP2B1-4 | Protein | REACT_24662 (Reactome) | |
| ATP | Metabolite | CHEBI:15422 (ChEBI) | |
| Activated
cGMP-dependent protein kinase (PKGs) | Complex | REACT_24034 (Reactome) | |
| BK channel, phophorylated | Complex | REACT_24816 (Reactome) | BK channels (also called Maxi-K or slo1) are potassium ion channels. They are activated by changes in membrane electrical potential and increases in intracellular [Ca2+]. Opening of BK channels results in cell membrane hyperpolarization. BK channels are tetramers of dimer subunits formed by the association of a pore-forming alpha subunit, always derived from the same gene KCNMA1, and a modulatory beta subunit, dervied from one of 4 human genes KCNMB11-4. Intracellular calcium regulates the physical association between the alpha and beta subunits. |
| BK channel | Complex | REACT_24118 (Reactome) | BK channels (also called Maxi-K or slo1) are potassium ion channels. They are activated by changes in membrane electrical potential and increases in intracellular [Ca2+]. Opening of BK channels results in cell membrane hyperpolarization. BK channels are tetramers of dimer subunits formed by the association of a pore-forming alpha subunit, always derived from the same gene KCNMA1, and a modulatory beta subunit, dervied from one of 4 human genes KCNMB11-4. Intracellular calcium regulates the physical association between the alpha and beta subunits. |
| CHEST [extracellular region] | Metabolite | CHEBI:17002 (ChEBI) | |
| CHOL [extracellular region] | Metabolite | CHEBI:16113 (ChEBI) | |
| CRAC channel | Complex | REACT_24443 (Reactome) | |
| Ca2+ [platelet dense
tubular network membrane] | Metabolite | CHEBI:29108 (ChEBI) | |
| Ca2+ | Metabolite | CHEBI:29108 (ChEBI) | |
| Cations | Metabolite | REACT_24030 (Reactome) | |
| Cations | Metabolite | REACT_24868 (Reactome) | |
| Cyclic GMP-dependent
protein kinases (PKGs) | Protein | REACT_24186 (Reactome) | |
| DAG [plasma membrane] | Metabolite | CHEBI:17815 (ChEBI) | |
| DAG-activated TRPC3/6/7 | Complex | REACT_24061 (Reactome) | |
| FGR [cytosol] | Protein | P09769 (Uniprot-TrEMBL) | |
| FGR | Protein | P09769 (Uniprot-TrEMBL) | |
| G-protein alpha (s):GTP | Complex | REACT_5470 (Reactome) | |
| G-protein beta-gamma complex | Complex | REACT_15674 (Reactome) | |
| GDP [plasma membrane] | Metabolite | CHEBI:17552 (ChEBI) | |
| GDP | Metabolite | CHEBI:17552 (ChEBI) | |
| GMP | Metabolite | CHEBI:17345 (ChEBI) | |
| GNAS(2-394) [plasma membrane] | Protein | P63092 (Uniprot-TrEMBL) | |
| GTP [plasma membrane] | Metabolite | CHEBI:15996 (ChEBI) | |
| GTP | Metabolite | CHEBI:15996 (ChEBI) | |
| GUCY1A2 [cytosol] | Protein | P33402 (Uniprot-TrEMBL) | |
| GUCY1A3 [cytosol] | Protein | Q02108 (Uniprot-TrEMBL) | |
| GUCY1B2 [cytosol] | Protein | O75343 (Uniprot-TrEMBL) | |
| GUCY1B3 [cytosol] | Protein | Q02153 (Uniprot-TrEMBL) | |
| Guanylate cyclase, soluble | Complex | REACT_24123 (Reactome) | |
| Guanylate cyclase:NO | Complex | REACT_24768 (Reactome) | |
| H+ | Metabolite | CHEBI:15378 (ChEBI) | |
| Heterotrimeric
G-protein Gs (inactive) | Complex | REACT_18222 (Reactome) | |
| I(1,4,5)P3 [platelet
dense tubular network membrane] | Metabolite | CHEBI:16595 (ChEBI) | |
| IP receptor:Prostacyclin | Complex | REACT_17421 (Reactome) | |
| IP3 receptor bound to IP3 and Ca++ | Complex | REACT_4346 (Reactome) | |
| IRAG:ITPR1 | Complex | REACT_24389 (Reactome) | |
| ITPR1 [platelet
dense tubular network membrane] | Protein | Q14643 (Uniprot-TrEMBL) | |
| ITPR2 [platelet
dense tubular network membrane] | Protein | Q14571 (Uniprot-TrEMBL) | |
| ITPR3 [platelet
dense tubular network membrane] | Protein | Q14573 (Uniprot-TrEMBL) | |
| KCNMA1 [plasma membrane] | Protein | Q12791 (Uniprot-TrEMBL) | |
| KCNMB1 [plasma membrane] | Protein | Q16558 (Uniprot-TrEMBL) | |
| KCNMB2 [plasma membrane] | Protein | Q9Y691 (Uniprot-TrEMBL) | |
| KCNMB3 [plasma membrane] | Protein | Q9NPA1 (Uniprot-TrEMBL) | |
| KCNMB4 [plasma membrane] | Protein | Q86W47 (Uniprot-TrEMBL) | |
| L-Arg | Metabolite | CHEBI:16467 (ChEBI) | |
| L-Cit | Metabolite | CHEBI:16349 (ChEBI) | |
| LDL:LRP8 | Complex | REACT_24595 (Reactome) | |
| LDL:p-LRP8:FGR | Complex | REACT_24077 (Reactome) | |
| LDL | Complex | REACT_7774 (Reactome) | LDL (low density lipoproteins) are complexes of a single molecule of apoprotein B-100 (apoB-100) non-covalently associated with triacylglycerol, free cholesterol, cholesterol esters, and phospholipids. LDL complexes contain single molecules of apoB-100, but their content of lipids is variable (Chapman et al. 1988; Mateu et al. 1972; Tardieu et al. 1976). High levels of LDL in the blood are strongly correlated with increased risk of atherosclerosis, and recent studies have raised the possibility that this risk is further increased in individuals whose blood LDL population is enriched in high-density (low lipid content) LDL complexes (Rizzo and Berneis 2006). The LDL complex annotated here contains an average lipid composition. |
| LRP8 [plasma membrane] | Protein | Q14114 (Uniprot-TrEMBL) | |
| LRP8 | Protein | Q14114 (Uniprot-TrEMBL) | |
| MAPK14 | Protein | Q16539 (Uniprot-TrEMBL) | |
| MRVI1 [platelet
dense tubular network membrane] | Protein | Q9Y6F6 (Uniprot-TrEMBL) | |
| Mg2+ [cytosol] | Metabolite | CHEBI:18420 (ChEBI) | |
| NADP+ | Metabolite | CHEBI:18009 (ChEBI) | |
| NADPH | Metabolite | CHEBI:16474 (ChEBI) | |
| NO [cytosol] | Metabolite | CHEBI:16480 (ChEBI) | |
| NO | Metabolite | CHEBI:16480 (ChEBI) | |
| Na+/Ca2+ exchanger proteins | Protein | REACT_20277 (Reactome) | |
| Na+ | Metabolite | CHEBI:29101 (ChEBI) | |
| Nitric oxide synthase | Protein | REACT_24417 (Reactome) | |
| O2 | Metabolite | CHEBI:15379 (ChEBI) | |
| ORAI1 [plasma membrane] | Protein | Q96D31 (Uniprot-TrEMBL) | |
| Orai1 dimer | Complex | REACT_24301 (Reactome) | |
| P2RX1 [plasma membrane] | Protein | P51575 (Uniprot-TrEMBL) | |
| P2RX1 | Protein | P51575 (Uniprot-TrEMBL) | |
| P2X1 purinoreceptor bound to ATP | Complex | REACT_3044 (Reactome) | P2X1 protein readily forms stable trimers and hexamers, suggesting that the intact receptor is a multimer of three or six subunits in heterologous expression systems. However,assembly in native cells may be influenced significantly by associated proteins that are not present in heterologous expression systems. |
| PECAM-1:SHP-1 complex | Complex | REACT_13228 (Reactome) | |
| PECAM-1:SHP-2 complex | Complex | REACT_13041 (Reactome) | |
| PGI2 [extracellular region] | Metabolite | CHEBI:15552 (ChEBI) | |
| PGI2 | Metabolite | CHEBI:15552 (ChEBI) | |
| PL [extracellular region] | Metabolite | CHEBI:16247 (ChEBI) | |
| PLA2G4A | Protein | P47712 (Uniprot-TrEMBL) | |
| PP2A | Complex | REACT_10628 (Reactome) | |
| PPi | Metabolite | CHEBI:29888 (ChEBI) | |
| PRKG1-1 [cytosol] | Protein | Q13976-1 (Uniprot-TrEMBL) | |
| PRKG2 [cytosol] | Protein | Q13237 (Uniprot-TrEMBL) | |
| PTGIR [plasma membrane] | Protein | P43119 (Uniprot-TrEMBL) | |
| PTGIR | Protein | P43119 (Uniprot-TrEMBL) | |
| PTPN11 [cytosol] | Protein | Q06124 (Uniprot-TrEMBL) | |
| PTPN11 | Protein | Q06124 (Uniprot-TrEMBL) | |
| PTPN6 [cytosol] | Protein | P29350 (Uniprot-TrEMBL) | |
| PTPN6 | Protein | P29350 (Uniprot-TrEMBL) | |
| Phosphorylated
IRAG:IP3 receptor type 1 | Complex | REACT_24181 (Reactome) | |
| Prostacyclin:prostacyclin
receptor:G-protein Gs (active) | Complex | REACT_24753 (Reactome) | |
| Prostacyclin:prostacyclin
receptor:Gs (inactive) | Complex | REACT_24060 (Reactome) | |
| STIM1 Dimer | Complex | REACT_27372 (Reactome) | |
| STIM1 [endoplasmic reticulum membrane] | Protein | Q13586 (Uniprot-TrEMBL) | |
| STIM1 | Protein | Q13586 (Uniprot-TrEMBL) | |
| TAGs [extracellular region] | Metabolite | CHEBI:17855 (ChEBI) | |
| TRPC3(1-848) [plasma membrane] | Protein | Q13507 (Uniprot-TrEMBL) | |
| TRPC6 [plasma membrane] | Protein | Q9Y210 (Uniprot-TrEMBL) | |
| TRPC7 [plasma membrane] | Protein | Q9HCX4 (Uniprot-TrEMBL) | |
| cGMP phosphodiesterases | Protein | REACT_24101 (Reactome) | |
| cGMP [cytosol] | Metabolite | CHEBI:16356 (ChEBI) | |
| cGMP | Metabolite | CHEBI:16356 (ChEBI) | |
| p-PECAM:PP2A | Complex | REACT_24470 (Reactome) | |
| p-S1195-KCNMA1 [plasma membrane] | Protein | Q12791 (Uniprot-TrEMBL) | |
| p-S505,S727-PLA2G4A | Protein | P47712 (Uniprot-TrEMBL) | |
| p-S657,S670-MRVI1
[platelet dense tubular network membrane] | Protein | Q9Y6F6 (Uniprot-TrEMBL) | |
| p-T180,Y182-MAPK14 | Protein | Q16539 (Uniprot-TrEMBL) | |
| p-Y-LRP8 [plasma membrane] | Protein | Q14114 (Uniprot-TrEMBL) | |
| p-Y663,Y686-PECAM1(27-?) [plasma membrane] | Protein | P16284 (Uniprot-TrEMBL) | |
| p-Y663,Y686-PECAM1(27-?) | Protein | P16284 (Uniprot-TrEMBL) |
Annotated Interactions
| View all... |
| Source | Target | Type | Database reference | Comment |
|---|---|---|---|---|
| ADP | Arrow | REACT_20541 (Reactome) | ||
| ADP | Arrow | REACT_23918 (Reactome) | ||
| ADP | Arrow | REACT_23951 (Reactome) | ||
| ATP2A1-3 | mim-catalysis | REACT_23784 (Reactome) | ||
| ATP2B1-4 | mim-catalysis | REACT_23956 (Reactome) | ||
| ATP | REACT_20541 (Reactome) | |||
| ATP | REACT_23915 (Reactome) | |||
| ATP | REACT_23918 (Reactome) | |||
| ATP | REACT_23951 (Reactome) | |||
| Activated
cGMP-dependent protein kinase (PKGs) | Arrow | REACT_23934 (Reactome) | ||
| BK channel, phophorylated | Arrow | REACT_23991 (Reactome) | ||
| BK channel | REACT_23991 (Reactome) | |||
| CRAC channel | Arrow | REACT_23904 (Reactome) | ||
| CRAC channel | mim-catalysis | REACT_23967 (Reactome) | ||
| Ca2+ | Arrow | REACT_118637 (Reactome) | ||
| Ca2+ | Arrow | REACT_19164 (Reactome) | ||
| Ca2+ | Arrow | REACT_23784 (Reactome) | ||
| Ca2+ | Arrow | REACT_23956 (Reactome) | ||
| Ca2+ | Arrow | REACT_23967 (Reactome) | ||
| Ca2+ | Arrow | REACT_500 (Reactome) | ||
| Ca2+ | REACT_118637 (Reactome) | |||
| Ca2+ | REACT_19164 (Reactome) | |||
| Ca2+ | REACT_23784 (Reactome) | |||
| Ca2+ | REACT_23956 (Reactome) | |||
| Ca2+ | REACT_23967 (Reactome) | |||
| Ca2+ | REACT_500 (Reactome) | |||
| Cations | Arrow | REACT_23771 (Reactome) | ||
| Cations | REACT_23771 (Reactome) | |||
| Cyclic GMP-dependent
protein kinases (PKGs) | REACT_23934 (Reactome) | |||
| Cyclic GMP-dependent
protein kinases (PKGs) | mim-catalysis | REACT_23991 (Reactome) | ||
| Cyclic GMP-dependent
protein kinases (PKGs) | mim-catalysis | REACT_24000 (Reactome) | ||
| DAG-activated TRPC3/6/7 | mim-catalysis | REACT_23771 (Reactome) | ||
| FGR | REACT_23918 (Reactome) | |||
| FGR | mim-catalysis | REACT_23918 (Reactome) | ||
| FGR | mim-catalysis | REACT_23951 (Reactome) | ||
| G-protein alpha (s):GTP | Arrow | REACT_23792 (Reactome) | ||
| G-protein beta-gamma complex | Arrow | REACT_23792 (Reactome) | ||
| GDP | Arrow | REACT_23823 (Reactome) | ||
| GMP | Arrow | REACT_23959 (Reactome) | ||
| GTP | REACT_23790 (Reactome) | |||
| GTP | REACT_23823 (Reactome) | |||
| Guanylate cyclase, soluble | REACT_23945 (Reactome) | |||
| Guanylate cyclase:NO | Arrow | REACT_23945 (Reactome) | ||
| Guanylate cyclase:NO | mim-catalysis | REACT_23790 (Reactome) | ||
| H+ | Arrow | REACT_23784 (Reactome) | ||
| H+ | REACT_23784 (Reactome) | |||
| Heterotrimeric
G-protein Gs (inactive) | REACT_23938 (Reactome) | |||
| IP receptor:Prostacyclin | Arrow | REACT_23795 (Reactome) | ||
| IP receptor:Prostacyclin | REACT_23938 (Reactome) | |||
| IP3 receptor bound to IP3 and Ca++ | mim-catalysis | REACT_118637 (Reactome) | ||
| IRAG:ITPR1 | REACT_24000 (Reactome) | |||
| L-Arg | REACT_23872 (Reactome) | |||
| L-Cit | Arrow | REACT_23872 (Reactome) | ||
| LDL:LRP8 | Arrow | REACT_23972 (Reactome) | ||
| LDL:LRP8 | REACT_23918 (Reactome) | |||
| LDL:p-LRP8:FGR | Arrow | REACT_23918 (Reactome) | ||
| LDL | REACT_23906 (Reactome) | |||
| LDL | REACT_23972 (Reactome) | |||
| LRP8 | REACT_23972 (Reactome) | |||
| MAPK14 | REACT_23951 (Reactome) | |||
| NADP+ | Arrow | REACT_23872 (Reactome) | ||
| NADPH | REACT_23872 (Reactome) | |||
| NO | Arrow | REACT_23790 (Reactome) | ||
| NO | Arrow | REACT_23872 (Reactome) | ||
| NO | REACT_23945 (Reactome) | |||
| Na+/Ca2+ exchanger proteins | mim-catalysis | REACT_19164 (Reactome) | ||
| Na+ | Arrow | REACT_19164 (Reactome) | ||
| Na+ | REACT_19164 (Reactome) | |||
| Nitric oxide synthase | mim-catalysis | REACT_23872 (Reactome) | ||
| O2 | REACT_23872 (Reactome) | |||
| Orai1 dimer | REACT_23904 (Reactome) | |||
| P2RX1 | REACT_23915 (Reactome) | |||
| P2X1 purinoreceptor bound to ATP | Arrow | REACT_23915 (Reactome) | ||
| P2X1 purinoreceptor bound to ATP | mim-catalysis | REACT_500 (Reactome) | ||
| PECAM-1:SHP-1 complex | Arrow | REACT_12552 (Reactome) | ||
| PECAM-1:SHP-2 complex | Arrow | REACT_12509 (Reactome) | ||
| PGI2 | Arrow | REACT_23792 (Reactome) | ||
| PGI2 | REACT_23795 (Reactome) | |||
| PLA2G4A | REACT_20541 (Reactome) | |||
| PP2A | REACT_23942 (Reactome) | |||
| PPi | Arrow | REACT_23790 (Reactome) | ||
| PTGIR | Arrow | REACT_23792 (Reactome) | ||
| PTGIR | REACT_23795 (Reactome) | |||
| PTPN11 | REACT_12509 (Reactome) | |||
| PTPN6 | REACT_12552 (Reactome) | |||
| Phosphorylated
IRAG:IP3 receptor type 1 | Arrow | REACT_24000 (Reactome) | ||
| Prostacyclin:prostacyclin
receptor:G-protein Gs (active) | Arrow | REACT_23823 (Reactome) | ||
| Prostacyclin:prostacyclin
receptor:G-protein Gs (active) | REACT_23792 (Reactome) | |||
| Prostacyclin:prostacyclin
receptor:Gs (inactive) | Arrow | REACT_23938 (Reactome) | ||
| Prostacyclin:prostacyclin
receptor:Gs (inactive) | REACT_23823 (Reactome) | |||
| Prostacyclin:prostacyclin
receptor:Gs (inactive) | mim-catalysis | REACT_23823 (Reactome) | ||
| REACT_118637 (Reactome) | The IP3 receptor (IP3R) is an intracellular calcium release channel that mobilizes Ca2+ from internal stores in the ER to the cytoplasm. Though its activity is stimulated by IP3, the principal activator of the IP3R is Ca2+. This process of calcium-induced calcium release is central to the mechanism of Ca2+ signalling. The effect of cytosolic Ca2+ on IP3R is complex: it can be both stimulatory and inhibitory and can the effect varies between IP3R isoforms. In general, the IP3Rs have a bell-shaped Ca2+ dependence when treated with low concentrations of IP3; low concentrations of Ca2+ (100–300 nM) are stimulatory but above 300 nM, Ca2+ becomes inhibitory and switches the channel off. The stimulatory effect of IP3 is to relieve Ca2+ inhibition of the channel, enabling Ca2+ activation sites to gate it. Functionally the IP3 receptor is believed to be tetrameric, with results indicating that the tetramer is composed of 2 pairs of protein isoforms. | |||
| REACT_12509 (Reactome) | PECAM-1 becomes tyrosine-phosphorylated during the platelet aggregation process; the phosphorylation of two tandem tyrosine residues (Y663 and Y686) within the cytoplasmic domain is required for downstream signalling events. Phosphorylation creates docking sites for the protein-tyrosine phosphatase SHP-2. The interaction between SHP-2 and PECAM-1 is dependent upon integrin-mediated platelet/platelet interactions and occurs via the Src homology 2 (SH2) domains of the phosphatase and highly conserved phosphatase-binding motifs encompassing phosphotyrosines 663 and 686 within the cytoplasmic domain of PECAM-1. | |||
| REACT_12552 (Reactome) | The phosphorylation of two tandem tyrosine residues (Y663 and Y686) within the cytoplasmic domain of PECAM-1 is required for the downstream signalling events observed following PECAM-1 ligation. Both SH2 domains of SHP-1 are required in tandem to bind PECAM-1. | |||
| REACT_19164 (Reactome) | The NCX (SCL8, Na+/Ca2+ exchanger) family is one of three families that control Ca2+ flux across the plasma membrane or intracellular compartments. They extrude Ca2+ from the cell, using the electrochemical gradient of Na+ as it flows into the cell. One Ca2+ is exchanged for three Na+. During this electrogenic exchange, the membrane potential is altered. NCX1 (SLC8A1) has a ubiquitous expression profile (highest expression in heart, brain and kidney) and was originally cloned and characterized from human cardiac muscle (Komuro I et al, 1992). Both NCX2 (SLC8A2) (Li Z et al, 1994) and NCX3 (SLC8A3) (Gabellini N et al, 2002) are expressed in the brain. | |||
| REACT_20541 (Reactome) | MAPK p38 alpha activates cPLA2 by phosphorylation of two serine residues. cPLA2 can be phosphorylated and activated by ERK2 (Lin et al. 1993), and were believed to be responsible for the phosphorylation of cPLA2. However, phosphorylation of cPLA2 occurred in the absence of ERK activation in human platelets stimulated with the thrombin receptor agonist peptide SFLLRN (Kramer et al. 1995), and cPLA2 phosphorylation induced by thrombin or collagen was unaffected by PKC inhibitors that prevent ERK activation (Börsch-Haubold et al. 1995). In addition, a specific inhibitor of ERKs did not block thrombin-induced cPLA2 phosphorylation (Börsch-Haubold et al. 1996). | |||
| REACT_23771 (Reactome) | TRP channels are non-selectively permeable to cations, allowing enty into the cell via concentration gradients. All mammalian TRPCs require PLC for activation. | |||
| REACT_23784 (Reactome) | Intracellular pools of Ca2+ serve as the source for inositol 1,4,5-trisphosphate (IP3) -induced alterations in cytoplasmic free Ca2+. In most human cells Ca2+ is stored in the lumen of the sarco/endoplastic reticulum by ATPases known as SERCAs (ATP2As). In platelets, ATP2As transport Ca2+ into the platelet dense tubular network. ATP2As are P-type ATPases, similar to the plasma membrane Na+ and Ca+-ATPases. Humans have three genes for SERCA pumps; ATP2A1-3. Studies on ATP2A1 suggest that it binds two Ca2+ ions from the cytoplasm and is subsequently phosphorylated at Asp351 before translocating Ca2+ into the SR lumen. There is a counter transport of two or possibly three protons ensuring partial charge balancing. | |||
| REACT_23790 (Reactome) | Soluble guanylate cyclase (sGC) is a heterodimeric hemoprotein that selectively binds Nitric Oxide (NO). NO binding stimulates the synthesis of cGMP, which then binds to phosphodiesterases (PDE), ion-gated channels, and cGMP-dependent protein kinases (cGK) to regulate several physiological functions including vasodilation, platelet aggregation and neurotransmission. | |||
| REACT_23792 (Reactome) | The classical view of G-protein signalling is that the G-protein alpha subunit dissociates from the beta:gamma dimer. Activated G alpha (s) and the beta:gamma dimer then participate in separate signaling cascades. Although G protein dissociation has been contested (e.g. Bassi et al. 1996), recent in vivo experiments have demonstrated that dissociation does occur, though possibly not to completion (Lambert 2008). | |||
| REACT_23795 (Reactome) | Prostacyclin binds the G-protein coupled prostacyclin receptor, often referred to as the IP receptor. | |||
| REACT_23823 (Reactome) | The G-protein alpha subunit exchanges GDP for GTP | |||
| REACT_23872 (Reactome) | Nitric oxide synthase (NOS) produces NO from L-arginine. There are three isoforms of NOS, endothelial, neuronal and inducible (eNOS, nNOS, and iNOS). eNOS and nNOS are constitutively expressed while iNOS is induced by immunostimulatory signals. The constitutive isoforms are regulated in vivo by the binding of calcium and calmodulin. NO produced by NOS acts as a signalling molecule by diffusing across cell membranes to activate soluble guanylate cyclase (sGC). | |||
| REACT_23904 (Reactome) | Sustained calcium signalling in lymphocytes and platelets requires the uptake of extracellular calcium when intracellular stores are depleted. The process whereby intracellular calcium depletion stimulates calcium uptake is often referred to as Store-operated calcium entry (SOCE). Store depletion is sensed by stromal interaction molecule 1 (STIM1), which then translocates to the plasma membrane and associates with 2 dimers of Orai1 to form a calcium-release activated calcium (CRAC) channel. | |||
| REACT_23906 (Reactome) | LDL causes a transient increase in p38 MAPK activity in platelets. After an initial phase in which LDL leads to the activation of p38MAPK, LDL leads to activation of PECAM-1, stimulating the Ser/Thr phosphatases PP1/PP2Aand reducing the activity of p38MAPK by dephosphorylation. | |||
| REACT_23915 (Reactome) | P2X receptors are a family of cation-permeable ligand gated ion channels that open in response to the binding of extracellular adenosine triphosphate (ATP). All members of the family are thought to be functionally trimeric. The ionotropic P2X1 receptor has relatively high calcium permeability. It is predominantly expressed in smooth muscle and platelets, but also has a role in synaptic transmission between neurons and from neurons to smooth muscle. Mouse studies suggest that this receptor is essential for normal male reproductive function. ADP has been suggested as a ligand for this receptor but this is no longer widely accepted. | |||
| REACT_23918 (Reactome) | Tyrosine phosphorylation of LDL:LRP8 is mediated by the Src-family kinase FGR, based on a correlation of increased LRP8 phosphorylation on LDL stimulation of platelets, and a transient increased co-precipitation of FGR with LRP8 upon LDL stimulation. | |||
| REACT_23934 (Reactome) | Protein Kinase G (PKG) is a homodimer held together by a leucine zipper present in the N terminus. Each member of the dimer has two cyclic GMP (cGMP) binding sites, one low affinity and one high affinity. PKG was first described in various arthropods. Mammals have two PKG genes, prkg1 and prkg2, that encode PKG1 (cGKI) and PKG2 (cGKII). The N terminus (the first 90-100 residues) of PKG1 is encoded by two alternatively spliced exons that produce the isoforms PKG1alpha and PKG1beta. Both are cytosolic. PKG1 is present in high concentrations (>0.1 µM) in all smooth muscles, platelets, cerebellum, hippocampus, dorsal root ganglia, neuromuscular endplate, and kidney. PKG1beta is the predominant PKG isoform in platelets. PKG1 is required for the inhibition of platelet activation by NO/cGMP. PKG2 is anchored at the plasma membrane by myristoylation of the N-terminal Gly-2 residue. PKG2 phosphorylates cystic fibrosis transmembrane conductance regulator. | |||
| REACT_23938 (Reactome) | The human prostacyclin receptor (IP) and G-protein alpha (s) physically interact through contacts between the IP iLP1 domain and the C-terminal residues of the G alpha (s) protein. | |||
| REACT_23942 (Reactome) | PECAM-1 co-immunoprecipitates with PP2A | |||
| REACT_23945 (Reactome) | Soluble guanylate cyclase (sGC) is a heterodimeric hemoprotein that selectively binds Nitric Oxide (NO). NO binding stimulates the synthesis of cGMP, which then binds to phosphodiesterases (PDE), ion-gated channels, and cGMP-dependent protein kinases (cGK) to regulate several physiological functions including vasodilation, platelet aggregation and neurotransmission. | |||
| REACT_23951 (Reactome) | LDL stimulation of platelets leads to increased p38 MAPK activation by phosphorylation. An Src family kinase is responsible for this; Fgr is a strong candidate as it is known to bind the LDL receptor in platelets responding to LDL and in chemoattractant-induced degranulation of neutrophils activation of p38 MAPK is blocked by a triple Hck/Fgr/Lyn knockout. However fMLP-stimulated phosphorylation of MAPKs in a double hck/fgr PMNs was observed to be normal, suggesting that Lyn, rather than Fyn, is involved. | |||
| REACT_23956 (Reactome) | The plasma membrane Ca-ATPases 1-4 (ATP2B1-4, PMCAs) are P-type Ca2+-ATPases regulated by calmodulin. The PMCA also counter-transports a proton. PMCA is important for Ca2+ homeostasis and function. | |||
| REACT_23959 (Reactome) | Cyclic GMP phosphodiesterase are hydrolases selective for cAMP (PDE4, 7 and 8), cGMP (PDE5, 6 and 9) or able to hydrolyse both cAMP and cGMP (PDE1, 2, 3, 10 and 11). Â The dual-specificity PDEs allow for cross-regulation of the cAMP and cGMP pathways, e.g. PDE2 can hydrolyse both, but binding of cGMP to the regulatory GAF-B domain increases cAMP affinity and hydrolysis. PDE2, 3 and 5 are expressed in platelets. | |||
| REACT_23967 (Reactome) | Activation of Calcium-release-activated (CRAC) channels allows influx of calcium. The Orai component of CRAC is responsible for the selectivity of the channel, while the Stim component is responsible for activation. | |||
| REACT_23972 (Reactome) | LPR8 (apoER2) is the platelet low density lipoprotein (LDL) receptor. Mice lacking ApoE develop hypercholesterolemia and later atherosclerosis (Zhang et al. 1992). Similiar results are seen in familial hypercholesterolemia, where defective apoB/E receptors fail to remove LDL from the circulation. | |||
| REACT_23991 (Reactome) | NO-induced activation of cGMP-dependent protein kinase (PKG) increases the open probability of large conductance Ca2+-activated K+ channels (BK channels) by direct phosphorylation. | |||
| REACT_24000 (Reactome) | IRAG, PKG1(cGKI), and IP3 receptor type 1 can be isolated as a complex in human platelets. Phosphorylation of IRAG by PKG1 inhibits IP3 receptor-mediated Ca2+ release, representing the primary mechanism by which NO suppresses platelet activation. | |||
| REACT_500 (Reactome) | The P2X1 receptor is a rapidly-desensitized ATP-gated cation channel with relatively high calcium permeability. It has highest expression in smooth muscle and platelets. P2X1 receptor activation cannot induce platelet aggregation but does contribute to aggregation seen in response to collagen (Oury et al. 2001; Hechler et al. 2003). The role of P2X1 is more significant under flow conditions characterized by high shear stress (Hechler et al. 2003; Oury et al. 2004). P2X1 knockout mice havereduced incidence of thrombosis of mesenteric arterioles triggered by laser-induced vessel wall injury and are resistant to the acute systemic thromboembolism induced by infusion of a mixture of collagen and adrenaline (Hechler et al. 2003). Conversely, increased systemic thrombosis has been reported in mice overexpressing the human P2X1 receptor (Oury et al. 2003). P2X1 binding to ATP mediates synaptic transmission between neurons and from neurons to smooth muscle, controlling sympathetic vasoconstriction in small arteries, arterioles and vas deferens. | |||
| STIM1 Dimer | REACT_23904 (Reactome) | |||
| cGMP phosphodiesterases | mim-catalysis | REACT_23959 (Reactome) | ||
| cGMP | Arrow | REACT_23790 (Reactome) | ||
| cGMP | REACT_23934 (Reactome) | |||
| cGMP | REACT_23959 (Reactome) | |||
| p-PECAM:PP2A | Arrow | REACT_23942 (Reactome) | ||
| p-S505,S727-PLA2G4A | Arrow | REACT_20541 (Reactome) | ||
| p-T180,Y182-MAPK14 | Arrow | REACT_23951 (Reactome) | ||
| p-T180,Y182-MAPK14 | mim-catalysis | REACT_20541 (Reactome) | ||
| p-Y663,Y686-PECAM1(27-?) | Arrow | REACT_23906 (Reactome) | ||
| p-Y663,Y686-PECAM1(27-?) | REACT_12509 (Reactome) | |||
| p-Y663,Y686-PECAM1(27-?) | REACT_12552 (Reactome) | |||
| p-Y663,Y686-PECAM1(27-?) | REACT_23942 (Reactome) |
