Platelet homeostasis (Homo sapiens)

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9121327, 311, 2, 327, 20, 2510, 162115, 29306, 17, 242311, 2651828133, 14224, 342183319PP2A Activated cGMP-dependent protein kinase Phosphorylated IRAGIP3 receptor type 1 STIM1 Dimer STIM1 Dimer cytosolGuanylate cyclase soluble subunit alpha Prostacyclinprostacyclin receptorGs CRAC channel IP3 receptor platelet dense tubular network lumenLDL G-protein beta-gamma complex BK channel beta subunit LDLp-LRP8FGR Prostacyclinprostacyclin receptorG-protein Gs IP3R subunits IP receptorProstacyclin Heterotrimeric G-protein Gs G-protein beta-gamma complex G-protein beta-gamma complex IP3 receptor bound to IP3 and Ca++ Guanylate cyclase, soluble DAG-activated TRPC3/6/7 Heterotrimeric G-protein Gs PECAM-1SHP-1 complex LDLLRP8 Guanylate cyclase soluble subunit alpha Orai1 dimer G-protein alpha IP receptorProstacyclin Heterotrimeric G-protein Gs LDLp-LRP8 Cyclic GMP-dependent protein kinases Guanylate cyclase soluble subunit beta PP2A TRPC3/6/7 endoplasmic reticulum lumenGuanylate cyclase, soluble LDL p-PECAMPP2A BK channel beta subunit BK channel, phophorylated Guanylate cyclaseNO G-protein alpha P2X1 purinoreceptor bound to ATP PECAM-1SHP-2 complex IRAGITPR1 IP receptorProstacyclin BK channel Orai1 dimer Guanylate cyclase soluble subunit beta G-protein alpha LDL G-protein alpha G-protein beta-gamma complex P2RX1GUCY1B3 LDLp-LRP8FGRTAGs MRVI1 GNASATPITPR3 APOBcGMP p-Y663,Y686-PECAM1APOBORAI1 p-S657,S670-MRVI1 Ca2+TAGs NOPPiP2X1 purinoreceptor bound to ATPGUCY1B3 KCNMB1 ITPR1 ORAI1 GUCY1A3 PTGIRPGI2KCNMB3 PL BK channelMg2+ Guanylate cyclaseNOSTIM1Orai1 dimercGMPBK channel, phophorylatedFGR LDLTRPC6 KCNMB4 Mg2+ TRPC3PRKG2 GDPLRP8KCNMA1 ITPR1 p-Y663,Y686-PECAM1CationsFGRGNAScGMP phosphodiesterasesLRP8 Phosphorylated IRAGIP3 receptor type 1GUCY1A2 Na+Guanylate cyclase, solublep-S1195-KCNMA1 CRAC channelCHOL PL H+ATP2A1-3ATP IRAGITPR1CHEST GDP Activated cGMP-dependent protein kinase GNASCHEST IGTP ATPG-protein alpha KCNMB4 GMPNa+/Ca2+ exchanger proteinsp-Y663,Y686-PECAM1PLA2G4ADAG GTPGTPNO DAG-activated TRPC3/6/7KCNMB2 STIM1 PL ITPR1 GUCY1A3 H+GUCY1B2 PTGIR STIM1 DimerL-ArgIP3 receptor bound to IP3 and Ca++MAPK14PTGIR CHOL GUCY1A2 ADPGDP STIM1 GTP PP2ACa2+PTGIR Ca2+ CationsPGI2 PGI2 CHEST KCNMB2 PTPN11 PTPN6 p-Y-LRP8 L-CitO2Prostacyclinprostacyclin receptorGs TRPC7 NADPHATPPECAM-1SHP-2 complexGUCY1B2 p-S505,S727-PLA2G4Ap-PECAMPP2AITPR2 NADP+KCNMB3 APOBP2RX1 Na+G-protein beta-gamma complexPECAM-1SHP-1 complexPGI2 PTPN6Prostacyclinprostacyclin receptorG-protein Gs Nitric oxide synthaseATPPTPN11CHOL p-T180,Y182-MAPK14Cyclic GMP-dependent protein kinases ATP2B1-4p-Y663,Y686-PECAM1Heterotrimeric G-protein Gs Ca2+KCNMB1 LDLLRP8PRKG1-1 IP receptorProstacyclinGNASTAGs


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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Bibliography

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History

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CompareRevisionActionTimeUserComment
114759view16:24, 25 January 2021ReactomeTeamReactome version 75
113203view11:27, 2 November 2020ReactomeTeamReactome version 74
112428view15:37, 9 October 2020ReactomeTeamReactome version 73
101332view11:22, 1 November 2018ReactomeTeamreactome version 66
100870view20:55, 31 October 2018ReactomeTeamreactome version 65
100411view19:28, 31 October 2018ReactomeTeamreactome version 64
99960view16:13, 31 October 2018ReactomeTeamreactome version 63
99515view14:46, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99157view12:41, 31 October 2018ReactomeTeamreactome version 62
93869view13:42, 16 August 2017ReactomeTeamreactome version 61
93435view11:23, 9 August 2017ReactomeTeamreactome version 61
88100view09:31, 26 July 2016RyanmillerOntology Term : 'homeostasis pathway' added !
88099view09:30, 26 July 2016RyanmillerOntology Term : 'regulatory pathway' added !
86527view09:20, 11 July 2016ReactomeTeamreactome version 56
83192view10:19, 18 November 2015ReactomeTeamVersion54
81566view13:06, 21 August 2015ReactomeTeamVersion53
77031view08:33, 17 July 2014ReactomeTeamFixed remaining interactions
76736view12:09, 16 July 2014ReactomeTeamFixed remaining interactions
76061view10:12, 11 June 2014ReactomeTeamRe-fixing comment source
75771view11:28, 10 June 2014ReactomeTeamReactome 48 Update
75121view14:07, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74768view08:51, 30 April 2014ReactomeTeamReactome46
72011view12:23, 24 October 2013EgonwMore Uniprot-TrEMBL data source fixes.
72010view12:21, 24 October 2013EgonwFixed the Uniprot-TrEMBL data source.
42101view21:57, 4 March 2011MaintBotAutomatic update
39911view05:56, 21 January 2011MaintBotNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:16761 (ChEBI)
APOBProteinP04114 (Uniprot-TrEMBL)
ATP MetaboliteCHEBI:15422 (ChEBI)
ATP2A1-3ProteinREACT_24286 (Reactome)
ATP2B1-4ProteinREACT_24662 (Reactome)
ATPMetaboliteCHEBI:15422 (ChEBI)
Activated cGMP-dependent protein kinase ComplexREACT_24034 (Reactome)
BK channel, phophorylatedComplexREACT_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 channelComplexREACT_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 MetaboliteCHEBI:17002 (ChEBI)
CHOL MetaboliteCHEBI:16113 (ChEBI)
CRAC channelComplexREACT_24443 (Reactome)
Ca2+ MetaboliteCHEBI:29108 (ChEBI)
Ca2+MetaboliteCHEBI:29108 (ChEBI)
CationsMetaboliteREACT_24030 (Reactome)
CationsMetaboliteREACT_24868 (Reactome)
Cyclic GMP-dependent protein kinases ProteinREACT_24186 (Reactome)
DAG MetaboliteCHEBI:17815 (ChEBI)
DAG-activated TRPC3/6/7ComplexREACT_24061 (Reactome)
FGR ProteinP09769 (Uniprot-TrEMBL)
FGRProteinP09769 (Uniprot-TrEMBL)
G-protein alpha ComplexREACT_5470 (Reactome)
G-protein beta-gamma complexComplexREACT_15674 (Reactome)
GDP MetaboliteCHEBI:17552 (ChEBI)
GDPMetaboliteCHEBI:17552 (ChEBI)
GMPMetaboliteCHEBI:17345 (ChEBI)
GNASProteinP63092 (Uniprot-TrEMBL)
GTP MetaboliteCHEBI:15996 (ChEBI)
GTPMetaboliteCHEBI:15996 (ChEBI)
GUCY1A2 ProteinP33402 (Uniprot-TrEMBL)
GUCY1A3 ProteinQ02108 (Uniprot-TrEMBL)
GUCY1B2 ProteinO75343 (Uniprot-TrEMBL)
GUCY1B3 ProteinQ02153 (Uniprot-TrEMBL)
Guanylate cyclase NOComplexREACT_24768 (Reactome)
Guanylate cyclase, solubleComplexREACT_24123 (Reactome)
H+MetaboliteCHEBI:15378 (ChEBI)
Heterotrimeric G-protein Gs ComplexREACT_18222 (Reactome)
IMetaboliteCHEBI:16595 (ChEBI)
IP receptor ProstacyclinComplexREACT_17421 (Reactome)
IP3 receptor bound to IP3 and Ca++ComplexREACT_4346 (Reactome)
IRAG ITPR1ComplexREACT_24389 (Reactome)
ITPR1 ProteinQ14643 (Uniprot-TrEMBL)
ITPR2 ProteinQ14571 (Uniprot-TrEMBL)
ITPR3 ProteinQ14573 (Uniprot-TrEMBL)
KCNMA1 ProteinQ12791 (Uniprot-TrEMBL)
KCNMB1 ProteinQ16558 (Uniprot-TrEMBL)
KCNMB2 ProteinQ9Y691 (Uniprot-TrEMBL)
KCNMB3 ProteinQ9NPA1 (Uniprot-TrEMBL)
KCNMB4 ProteinQ86W47 (Uniprot-TrEMBL)
L-ArgMetaboliteCHEBI:16467 (ChEBI)
L-CitMetaboliteCHEBI:16349 (ChEBI)
LDL LRP8ComplexREACT_24595 (Reactome)
LDL

p-LRP8

FGR		ComplexREACT_24077 (Reactome)
LDLComplexREACT_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 ProteinQ14114 (Uniprot-TrEMBL)
LRP8ProteinQ14114 (Uniprot-TrEMBL)
MAPK14ProteinQ16539 (Uniprot-TrEMBL)
MRVI1 ProteinQ9Y6F6 (Uniprot-TrEMBL)
Mg2+ MetaboliteCHEBI:18420 (ChEBI)
NADP+MetaboliteCHEBI:18009 (ChEBI)
NADPHMetaboliteCHEBI:16474 (ChEBI)
NO MetaboliteCHEBI:16480 (ChEBI)
NOMetaboliteCHEBI:16480 (ChEBI)
Na+/Ca2+ exchanger proteinsProteinREACT_20277 (Reactome)
Na+MetaboliteCHEBI:29101 (ChEBI)
Nitric oxide synthaseProteinREACT_24417 (Reactome)
O2MetaboliteCHEBI:15379 (ChEBI)
ORAI1 ProteinQ96D31 (Uniprot-TrEMBL)
Orai1 dimerComplexREACT_24301 (Reactome)
P2RX1 ProteinP51575 (Uniprot-TrEMBL)
P2RX1ProteinP51575 (Uniprot-TrEMBL)
P2X1 purinoreceptor bound to ATPComplexREACT_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 complexComplexREACT_13228 (Reactome)
PECAM-1 SHP-2 complexComplexREACT_13041 (Reactome)
PGI2 MetaboliteCHEBI:15552 (ChEBI)
PGI2MetaboliteCHEBI:15552 (ChEBI)
PL MetaboliteCHEBI:16247 (ChEBI)
PLA2G4AProteinP47712 (Uniprot-TrEMBL)
PP2AComplexREACT_10628 (Reactome)
PPiMetaboliteCHEBI:29888 (ChEBI)
PRKG1-1 ProteinQ13976-1 (Uniprot-TrEMBL)
PRKG2 ProteinQ13237 (Uniprot-TrEMBL)
PTGIR ProteinP43119 (Uniprot-TrEMBL)
PTGIRProteinP43119 (Uniprot-TrEMBL)
PTPN11 ProteinQ06124 (Uniprot-TrEMBL)
PTPN11ProteinQ06124 (Uniprot-TrEMBL)
PTPN6 ProteinP29350 (Uniprot-TrEMBL)
PTPN6ProteinP29350 (Uniprot-TrEMBL)
Phosphorylated IRAG IP3 receptor type 1ComplexREACT_24181 (Reactome)
Prostacyclin

prostacyclin receptor

G-protein Gs 		ComplexREACT_24753 (Reactome)
Prostacyclin

prostacyclin receptor

Gs 		ComplexREACT_24060 (Reactome)
STIM1 DimerComplexREACT_27372 (Reactome)
STIM1 ProteinQ13586 (Uniprot-TrEMBL)
STIM1ProteinQ13586 (Uniprot-TrEMBL)
TAGs MetaboliteCHEBI:17855 (ChEBI)
TRPC3ProteinQ13507 (Uniprot-TrEMBL)
TRPC6 ProteinQ9Y210 (Uniprot-TrEMBL)
TRPC7 ProteinQ9HCX4 (Uniprot-TrEMBL)
cGMP MetaboliteCHEBI:16356 (ChEBI)
cGMP phosphodiesterasesProteinREACT_24101 (Reactome)
cGMPMetaboliteCHEBI:16356 (ChEBI)
p-PECAM PP2AComplexREACT_24470 (Reactome)
p-S1195-KCNMA1 ProteinQ12791 (Uniprot-TrEMBL)
p-S505,S727-PLA2G4AProteinP47712 (Uniprot-TrEMBL)
p-S657,S670-MRVI1 ProteinQ9Y6F6 (Uniprot-TrEMBL)
p-T180,Y182-MAPK14ProteinQ16539 (Uniprot-TrEMBL)
p-Y-LRP8 ProteinQ14114 (Uniprot-TrEMBL)
p-Y663,Y686-PECAM1ProteinP16284 (Uniprot-TrEMBL)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADPArrowREACT_20541 (Reactome)
ADPArrowREACT_23918 (Reactome)
ADPArrowREACT_23951 (Reactome)
ATP2A1-3REACT_23784 (Reactome)
ATP2B1-4REACT_23956 (Reactome)
ATPREACT_20541 (Reactome)
ATPREACT_23915 (Reactome)
ATPREACT_23918 (Reactome)
ATPREACT_23951 (Reactome)
CRAC channelREACT_23967 (Reactome)
Ca2+ArrowREACT_19164 (Reactome)
Ca2+ArrowREACT_23784 (Reactome)
Ca2+REACT_19164 (Reactome)
Ca2+REACT_23784 (Reactome)
Cyclic GMP-dependent protein kinases REACT_23934 (Reactome)
Cyclic GMP-dependent protein kinases REACT_23991 (Reactome)
Cyclic GMP-dependent protein kinases REACT_24000 (Reactome)
DAG-activated TRPC3/6/7REACT_23771 (Reactome)
FGRREACT_23918 (Reactome)
FGRREACT_23951 (Reactome)
G-protein alpha ArrowREACT_23792 (Reactome)
G-protein beta-gamma complexArrowREACT_23792 (Reactome)
GDPArrowREACT_23823 (Reactome)
GTPREACT_23823 (Reactome)
Guanylate cyclase NOREACT_23790 (Reactome)
Guanylate cyclase, solubleREACT_23945 (Reactome)
H+ArrowREACT_23784 (Reactome)
H+REACT_23784 (Reactome)
Heterotrimeric G-protein Gs REACT_23938 (Reactome)
IP receptor ProstacyclinREACT_23938 (Reactome)
IP3 receptor bound to IP3 and Ca++REACT_118637 (Reactome)
L-ArgREACT_23872 (Reactome)
L-CitArrowREACT_23872 (Reactome)
LDL LRP8REACT_23918 (Reactome)
LDL

p-LRP8

FGR		ArrowREACT_23918 (Reactome)
LDLREACT_23972 (Reactome)
LRP8REACT_23972 (Reactome)
MAPK14REACT_23951 (Reactome)
NADP+ArrowREACT_23872 (Reactome)
NADPHREACT_23872 (Reactome)
NOArrowREACT_23790 (Reactome)
NOArrowREACT_23872 (Reactome)
NOREACT_23945 (Reactome)
Na+/Ca2+ exchanger proteinsREACT_19164 (Reactome)
Na+ArrowREACT_19164 (Reactome)
Na+REACT_19164 (Reactome)
Nitric oxide synthaseREACT_23872 (Reactome)
O2REACT_23872 (Reactome)
Orai1 dimerREACT_23904 (Reactome)
P2RX1REACT_23915 (Reactome)
P2X1 purinoreceptor bound to ATPREACT_500 (Reactome)
PGI2ArrowREACT_23792 (Reactome)
PGI2REACT_23795 (Reactome)
PLA2G4AREACT_20541 (Reactome)
PP2AREACT_23942 (Reactome)
PPiArrowREACT_23790 (Reactome)
PTGIRArrowREACT_23792 (Reactome)
PTGIRREACT_23795 (Reactome)
PTPN11REACT_12509 (Reactome)
PTPN6REACT_12552 (Reactome)
Prostacyclin

prostacyclin receptor

G-protein Gs 		ArrowREACT_23823 (Reactome)
Prostacyclin

prostacyclin receptor

Gs 		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).  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 DimerREACT_23904 (Reactome)
cGMP phosphodiesterasesREACT_23959 (Reactome)
cGMPArrowREACT_23790 (Reactome)
cGMPREACT_23934 (Reactome)
p-S505,S727-PLA2G4AArrowREACT_20541 (Reactome)
p-T180,Y182-MAPK14ArrowREACT_23951 (Reactome)
p-T180,Y182-MAPK14REACT_20541 (Reactome)
p-Y663,Y686-PECAM1REACT_12509 (Reactome)
p-Y663,Y686-PECAM1REACT_12552 (Reactome)
p-Y663,Y686-PECAM1REACT_23942 (Reactome)
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