Platelet homeostasis (Homo sapiens)

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202, 4, 22312, 2576, 1581, 1839, 11312421, 26, 2714171923, 3230331610, 28, 2914513, 34endoplasmic reticulum lumencytosolplatelet dense tubular network lumenGNG2 GNB3 GNAS Na+ LRP8GNG10 PL Ca2+Mg2+ APOB(28-4563) PGI2 GNB4 GNG10 TAGs PTPN11 MRVI1 cGMPL-ArgCHOL p-S657,S670-MRVI1 APOB(28-4563) ATP2A1 SLC8A1 GUCY1A2 KCNMB4 GNB3 PPP2R1A GNB4 ATP2A3 GUCY1B2 ATP2B1-4PTPN6PPP2R5D PPP2R5C KCNMB4 CationsATP2B1 GNG12 P2RX1 GNG5 NOS3 GNB2 GNB5 STIM1 cGMP p-Y663,Y686-PECAM1(27-?)GNGT2 Na+ NOS1,2,3ITPR1 GNG7 GUCY1B3 GNB2 GNG3 PPP2R1B GNG11 GNG13 TRPC7 GNAS PGI2GNG4 GUCY1A3 PPP2CA TRPC3(1-848) H+P2RX1ATPATP2B3 NOGuanylate cyclase:NOPP2AActivatedcGMP-dependentprotein kinase(PKGs)GNG12 PPP2R5C NADP+ORAI1 p-T180,Y182-MAPK14GNB3 p-PECAM:PP2AGUCY1B2 PPP2CB GNB1 NADPHGUCY1B3 APOB(28-4563) p-S505,S727-PLA2G4Ap-Y663,Y686-PECAM1(27-?) STIM1 Mg2+ PPP2R5A GNG13 LDLDAG-activatedTRPC3/6/7GNG2 GNG11 ITPR3 I(1,4,5)P3 GNG2 ITPR1 PTPN11PPP2R5E Prostacyclin:prostacyclin receptor:Gs (inactive)LDL:LRP8GNGT1 MAPK14Na+GNB1 NO GNGT1 GNG10 IRAG:ITPR1PhosphorylatedIRAG:IP3 receptortype 1GNG13 GTPGUCY1A3 GNG13 GNG2 H+PPP2CB PL GNG5 GNG7 PPP2R5E GNG5 ATPGMPGNG11 KCNMB2 GNG4 KCNMB3 GNG3 p-Y663,Y686-PECAM1(27-?) PECAM-1:SHP-1complexG-protein beta-gammacomplexp-S1195-KCNMA1 TRPC6 G-protein alpha(s):GTPPTGIRPRKG2 GNG8 GNG3 GNB4 PGI2 GTP IPreceptor:ProstacyclinCa2+ Na+GTP GNB3 PPiGNG7 PPP2R5B ADPKCNMA1 GNGT2 L-CitDAG ATP2B2 KCNMB3 CationsGNG3 GUCY1A2 FGRp-Y-LRP8 ATP2B4 GNB5 GNG5 PRKG1-1 GNGT2 GNG12 GNB5 O2PTGIR Ca2+GNG4 GDP ATP2A2 STIM1 DimerPGI2 Mg2+ P2X1 purinoreceptorbound to ATPBK channel,phosphorylatedPRKG1-1 p-Y663,Y686-PECAM1(27-?) GNAS CHOL KCNMB2 BK channelLDL:p-LRP8:FGRGNGT1 Ca2+ FGR cGMPphosphodiesterasesITPR1 GDP ATPGNGT2 Ca2+ GNB4 Phosphodiesterases, dual (cAMP, cGMP) activity TAGs SLC8A3 Cyclic GMP-dependentprotein kinases(PKGs)HeterotrimericG-protein Gs(inactive)CRAC channelPTGIR PTPN6 GNB2 Orai1 dimerPPP2CA GNGT1 CHEST GTPCHEST GNB2 GNG8 GNG8 PLA2G4AGNG12 SLC8A1,2,3KCNMB1 PPP2R1B PL ITPR2 SLC8A2 KCNMB1 GNG4 PTGIR NOS1 LRP8 PPP2R5D IP3Rtetramer:I(1,4,5)P3:4xCa2+NOS2 PECAM-1:SHP-2complexPPP2R1A Prostacyclin:prostacyclin receptor:G-protein Gs (active)GNB5 TAGs GNG8 ATP ATP2A1-3GNG7 ATPCHOL GNAS PPP2R5A GDPGuanylate cyclase,solubleCHEST ORAI1 Phosphodiesterases, cyclic GMP-selective GNG10 GNB1 Ca2+PRKG2 GNG11 PPP2R5B GNB1 Mg2+


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.

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Bibliography

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History

View all...
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)
APOB(28-4563) ProteinP04114 (Uniprot-TrEMBL)
ATP MetaboliteCHEBI:15422 (ChEBI)
ATP2A1 ProteinO14983 (Uniprot-TrEMBL)
ATP2A1-3ComplexR-HSA-427905 (Reactome)
ATP2A2 ProteinP16615 (Uniprot-TrEMBL)
ATP2A3 ProteinQ93084 (Uniprot-TrEMBL)
ATP2B1 ProteinP20020 (Uniprot-TrEMBL)
ATP2B1-4ComplexR-HSA-418306 (Reactome)
ATP2B2 ProteinQ01814 (Uniprot-TrEMBL)
ATP2B3 ProteinQ16720 (Uniprot-TrEMBL)
ATP2B4 ProteinP23634 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:15422 (ChEBI)
Activated

cGMP-dependent protein kinase

(PKGs)		ComplexR-HSA-418378 (Reactome)
BK channel, phosphorylatedComplexR-HSA-418495 (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 channelComplexR-HSA-418473 (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 channelComplexR-HSA-434679 (Reactome)
Ca2+ MetaboliteCHEBI:29108 (ChEBI)
Ca2+MetaboliteCHEBI:29108 (ChEBI)
CationsComplexR-HSA-R-ALL-426219 (Reactome)
CationsComplexR-HSA-R-ALL-426221 (Reactome)
Cyclic GMP-dependent

protein kinases

(PKGs)		ComplexR-HSA-418379 (Reactome)
DAG MetaboliteCHEBI:17815 (ChEBI)
DAG-activated TRPC3/6/7ComplexR-HSA-426179 (Reactome)
FGR ProteinP09769 (Uniprot-TrEMBL)
FGRProteinP09769 (Uniprot-TrEMBL)
G-protein alpha (s):GTPComplexR-HSA-164358 (Reactome)
G-protein beta-gamma complexComplexR-HSA-167434 (Reactome)
GDP MetaboliteCHEBI:17552 (ChEBI)
GDPMetaboliteCHEBI:17552 (ChEBI)
GMPMetaboliteCHEBI:17345 (ChEBI)
GNAS ProteinP63092 (Uniprot-TrEMBL)
GNB1 ProteinP62873 (Uniprot-TrEMBL)
GNB2 ProteinP62879 (Uniprot-TrEMBL)
GNB3 ProteinP16520 (Uniprot-TrEMBL)
GNB4 ProteinQ9HAV0 (Uniprot-TrEMBL)
GNB5 ProteinO14775 (Uniprot-TrEMBL)
GNG10 ProteinP50151 (Uniprot-TrEMBL)
GNG11 ProteinP61952 (Uniprot-TrEMBL)
GNG12 ProteinQ9UBI6 (Uniprot-TrEMBL)
GNG13 ProteinQ9P2W3 (Uniprot-TrEMBL)
GNG2 ProteinP59768 (Uniprot-TrEMBL)
GNG3 ProteinP63215 (Uniprot-TrEMBL)
GNG4 ProteinP50150 (Uniprot-TrEMBL)
GNG5 ProteinP63218 (Uniprot-TrEMBL)
GNG7 ProteinO60262 (Uniprot-TrEMBL)
GNG8 ProteinQ9UK08 (Uniprot-TrEMBL)
GNGT1 ProteinP63211 (Uniprot-TrEMBL)
GNGT2 ProteinO14610 (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, solubleComplexR-HSA-392012 (Reactome)
Guanylate cyclase:NOComplexR-HSA-392141 (Reactome)
H+MetaboliteCHEBI:15378 (ChEBI)
Heterotrimeric

G-protein Gs

(inactive)		ComplexR-HSA-391179 (Reactome)
I(1,4,5)P3 MetaboliteCHEBI:16595 (ChEBI)
IP receptor:ProstacyclinComplexR-HSA-391929 (Reactome)
IP3R tetramer:I(1,4,5)P3:4xCa2+ComplexR-HSA-139839 (Reactome)
IRAG:ITPR1ComplexR-HSA-418425 (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:LRP8ComplexR-HSA-432119 (Reactome)
LDL:p-LRP8:FGRComplexR-HSA-432132 (Reactome)
LDLComplexR-HSA-171131 (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)
NOS1 ProteinP29475 (Uniprot-TrEMBL)
NOS1,2,3ComplexR-HSA-419294 (Reactome)
NOS2 ProteinP35228 (Uniprot-TrEMBL)
NOS3 ProteinP29474 (Uniprot-TrEMBL)
Na+ MetaboliteCHEBI:29101 (ChEBI)
Na+MetaboliteCHEBI:29101 (ChEBI)
O2MetaboliteCHEBI:15379 (ChEBI)
ORAI1 ProteinQ96D31 (Uniprot-TrEMBL)
Orai1 dimerComplexR-HSA-434696 (Reactome)
P2RX1 ProteinP51575 (Uniprot-TrEMBL)
P2RX1ProteinP51575 (Uniprot-TrEMBL)
P2X1 purinoreceptor bound to ATPComplexR-HSA-139848 (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 complexComplexR-HSA-210221 (Reactome)
PECAM-1:SHP-2 complexComplexR-HSA-210219 (Reactome)
PGI2 MetaboliteCHEBI:15552 (ChEBI)
PGI2MetaboliteCHEBI:15552 (ChEBI)
PL MetaboliteCHEBI:16247 (ChEBI)
PLA2G4AProteinP47712 (Uniprot-TrEMBL)
PP2AComplexR-HSA-196206 (Reactome)
PPP2CA ProteinP67775 (Uniprot-TrEMBL)
PPP2CB ProteinP62714 (Uniprot-TrEMBL)
PPP2R1A ProteinP30153 (Uniprot-TrEMBL)
PPP2R1B ProteinP30154 (Uniprot-TrEMBL)
PPP2R5A ProteinQ15172 (Uniprot-TrEMBL)
PPP2R5B ProteinQ15173 (Uniprot-TrEMBL)
PPP2R5C ProteinQ13362 (Uniprot-TrEMBL)
PPP2R5D ProteinQ14738 (Uniprot-TrEMBL)
PPP2R5E ProteinQ16537 (Uniprot-TrEMBL)
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)
Phosphodiesterases, cyclic GMP-selective R-HSA-418542 (Reactome)
Phosphodiesterases, dual (cAMP, cGMP) activity R-HSA-418547 (Reactome)
Phosphorylated

IRAG:IP3 receptor

type 1		ComplexR-HSA-418432 (Reactome)
Prostacyclin:prostacyclin receptor:G-protein Gs (active)ComplexR-HSA-392865 (Reactome)
Prostacyclin:prostacyclin receptor:Gs (inactive)ComplexR-HSA-392864 (Reactome)
SLC8A1 ProteinP32418 (Uniprot-TrEMBL)
SLC8A1,2,3ComplexR-HSA-425675 (Reactome)
SLC8A2 ProteinQ9UPR5 (Uniprot-TrEMBL)
SLC8A3 ProteinP57103 (Uniprot-TrEMBL)
STIM1 DimerComplexR-HSA-1168370 (Reactome)
STIM1 ProteinQ13586 (Uniprot-TrEMBL)
TAGs MetaboliteCHEBI:17855 (ChEBI)
TRPC3(1-848) ProteinQ13507 (Uniprot-TrEMBL)
TRPC6 ProteinQ9Y210 (Uniprot-TrEMBL)
TRPC7 ProteinQ9HCX4 (Uniprot-TrEMBL)
cGMP phosphodiesterasesComplexR-HSA-418560 (Reactome)
cGMP MetaboliteCHEBI:16356 (ChEBI)
cGMPMetaboliteCHEBI:16356 (ChEBI)
p-PECAM:PP2AComplexR-HSA-432144 (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-PECAM1(27-?) ProteinP16284 (Uniprot-TrEMBL)
p-Y663,Y686-PECAM1(27-?)ProteinP16284 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-428961 (Reactome)
ADPArrowR-HSA-432129 (Reactome)
ADPArrowR-HSA-432148 (Reactome)
ATP2A1-3mim-catalysisR-HSA-418365 (Reactome)
ATP2B1-4mim-catalysisR-HSA-418309 (Reactome)
ATPR-HSA-419490 (Reactome)
ATPR-HSA-428961 (Reactome)
ATPR-HSA-432129 (Reactome)
ATPR-HSA-432148 (Reactome)
Activated

cGMP-dependent protein kinase

(PKGs)		ArrowR-HSA-418451 (Reactome)
BK channel, phosphorylatedArrowR-HSA-418549 (Reactome)
BK channelR-HSA-418549 (Reactome)
CRAC channelArrowR-HSA-434700 (Reactome)
CRAC channelmim-catalysisR-HSA-434798 (Reactome)
Ca2+ArrowR-HSA-139854 (Reactome)
Ca2+ArrowR-HSA-139855 (Reactome)
Ca2+ArrowR-HSA-418309 (Reactome)
Ca2+ArrowR-HSA-418365 (Reactome)
Ca2+ArrowR-HSA-425661 (Reactome)
Ca2+ArrowR-HSA-434798 (Reactome)
Ca2+R-HSA-139854 (Reactome)
Ca2+R-HSA-139855 (Reactome)
Ca2+R-HSA-418309 (Reactome)
Ca2+R-HSA-418365 (Reactome)
Ca2+R-HSA-425661 (Reactome)
Ca2+R-HSA-434798 (Reactome)
CationsArrowR-HSA-426223 (Reactome)
CationsR-HSA-426223 (Reactome)
Cyclic GMP-dependent

protein kinases

(PKGs)		R-HSA-418451 (Reactome)
Cyclic GMP-dependent

protein kinases

(PKGs)		mim-catalysisR-HSA-418442 (Reactome)
Cyclic GMP-dependent

protein kinases

(PKGs)		mim-catalysisR-HSA-418549 (Reactome)
DAG-activated TRPC3/6/7mim-catalysisR-HSA-426223 (Reactome)
FGRR-HSA-432129 (Reactome)
FGRmim-catalysisR-HSA-432129 (Reactome)
FGRmim-catalysisR-HSA-432148 (Reactome)
G-protein alpha (s):GTPArrowR-HSA-392874 (Reactome)
G-protein beta-gamma complexArrowR-HSA-392874 (Reactome)
GDPArrowR-HSA-392870 (Reactome)
GMPArrowR-HSA-418456 (Reactome)
GTPR-HSA-392152 (Reactome)
GTPR-HSA-392870 (Reactome)
Guanylate cyclase, solubleR-HSA-392143 (Reactome)
Guanylate cyclase:NOArrowR-HSA-392143 (Reactome)
Guanylate cyclase:NOmim-catalysisR-HSA-392152 (Reactome)
H+ArrowR-HSA-418365 (Reactome)
H+R-HSA-418365 (Reactome)
Heterotrimeric

G-protein Gs

(inactive)		R-HSA-392852 (Reactome)
IP receptor:ProstacyclinArrowR-HSA-392849 (Reactome)
IP receptor:ProstacyclinR-HSA-392852 (Reactome)
IP3R tetramer:I(1,4,5)P3:4xCa2+mim-catalysisR-HSA-139854 (Reactome)
IRAG:ITPR1R-HSA-418442 (Reactome)
L-ArgR-HSA-418436 (Reactome)
L-CitArrowR-HSA-418436 (Reactome)
LDL:LRP8ArrowR-HSA-432121 (Reactome)
LDL:LRP8R-HSA-432129 (Reactome)
LDL:p-LRP8:FGRArrowR-HSA-432129 (Reactome)
LDLR-HSA-432121 (Reactome)
LDLR-HSA-435244 (Reactome)
LRP8R-HSA-432121 (Reactome)
MAPK14R-HSA-432148 (Reactome)
NADP+ArrowR-HSA-418436 (Reactome)
NADPHR-HSA-418436 (Reactome)
NOArrowR-HSA-392152 (Reactome)
NOArrowR-HSA-418436 (Reactome)
NOR-HSA-392143 (Reactome)
NOS1,2,3mim-catalysisR-HSA-418436 (Reactome)
Na+ArrowR-HSA-425661 (Reactome)
Na+R-HSA-425661 (Reactome)
O2R-HSA-418436 (Reactome)
Orai1 dimerR-HSA-434700 (Reactome)
P2RX1R-HSA-419490 (Reactome)
P2X1 purinoreceptor bound to ATPArrowR-HSA-419490 (Reactome)
P2X1 purinoreceptor bound to ATPmim-catalysisR-HSA-139855 (Reactome)
PECAM-1:SHP-1 complexArrowR-HSA-210277 (Reactome)
PECAM-1:SHP-2 complexArrowR-HSA-210294 (Reactome)
PGI2ArrowR-HSA-392874 (Reactome)
PGI2R-HSA-392849 (Reactome)
PLA2G4AR-HSA-428961 (Reactome)
PP2AR-HSA-432143 (Reactome)
PPiArrowR-HSA-392152 (Reactome)
PTGIRArrowR-HSA-392874 (Reactome)
PTGIRR-HSA-392849 (Reactome)
PTPN11R-HSA-210294 (Reactome)
PTPN6R-HSA-210277 (Reactome)
Phosphorylated

IRAG:IP3 receptor

type 1		ArrowR-HSA-418442 (Reactome)
Prostacyclin:prostacyclin receptor:G-protein Gs (active)ArrowR-HSA-392870 (Reactome)
Prostacyclin:prostacyclin receptor:G-protein Gs (active)R-HSA-392874 (Reactome)
Prostacyclin:prostacyclin receptor:Gs (inactive)ArrowR-HSA-392852 (Reactome)
Prostacyclin:prostacyclin receptor:Gs (inactive)R-HSA-392870 (Reactome)
Prostacyclin:prostacyclin receptor:Gs (inactive)mim-catalysisR-HSA-392870 (Reactome)
R-HSA-139854 (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.
R-HSA-139855 (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.
R-HSA-210277 (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.
R-HSA-210294 (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.
R-HSA-392143 (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.
R-HSA-392152 (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.
R-HSA-392849 (Reactome) Prostacyclin binds the G-protein coupled prostacyclin receptor, often referred to as the IP receptor.
R-HSA-392852 (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.
R-HSA-392870 (Reactome) The G-protein alpha subunit exchanges GDP for GTP
R-HSA-392874 (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).
R-HSA-418309 (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.
R-HSA-418365 (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.
R-HSA-418436 (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).
R-HSA-418442 (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.
R-HSA-418451 (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.
R-HSA-418456 (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.
R-HSA-418549 (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.
R-HSA-419490 (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.
R-HSA-425661 (Reactome) The sodium/calcium exchangers 1, 2 and 3 (SCL8A1,2,3 aka NCX1,2,3) belong to 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. SLC8A1 has a ubiquitous expression profile (highest expression in heart, brain and kidney) and was originally cloned and characterized from human cardiac muscle (Komuro et al. 1992). Both SLC8A2) (Li et al. 1994) and SLC8A3 (Gabellini et al. 2002) are expressed in the brain.
R-HSA-426223 (Reactome) TRP channels are non-selectively permeable to cations, allowing enty into the cell via concentration gradients. All mammalian TRPCs require PLC for activation.
R-HSA-428961 (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).
R-HSA-432121 (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.
R-HSA-432129 (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.
R-HSA-432143 (Reactome) PECAM-1 co-immunoprecipitates with PP2A
R-HSA-432148 (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.
R-HSA-434700 (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.
R-HSA-434798 (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.
R-HSA-435244 (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.
SLC8A1,2,3mim-catalysisR-HSA-425661 (Reactome)
STIM1 DimerR-HSA-434700 (Reactome)
cGMP phosphodiesterasesmim-catalysisR-HSA-418456 (Reactome)
cGMPArrowR-HSA-392152 (Reactome)
cGMPR-HSA-418451 (Reactome)
cGMPR-HSA-418456 (Reactome)
p-PECAM:PP2AArrowR-HSA-432143 (Reactome)
p-S505,S727-PLA2G4AArrowR-HSA-428961 (Reactome)
p-T180,Y182-MAPK14ArrowR-HSA-432148 (Reactome)
p-T180,Y182-MAPK14mim-catalysisR-HSA-428961 (Reactome)
p-Y663,Y686-PECAM1(27-?)ArrowR-HSA-435244 (Reactome)
p-Y663,Y686-PECAM1(27-?)R-HSA-210277 (Reactome)
p-Y663,Y686-PECAM1(27-?)R-HSA-210294 (Reactome)
p-Y663,Y686-PECAM1(27-?)R-HSA-432143 (Reactome)
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