Platelet homeostasis (Homo sapiens)

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12314, 208, 159, 4331519, 4125, 4212291126102664, 24, 33, 3718, 21, 363, 7, 13, 22, 356311628, 4032, 38, 4417, 27, 30, 34, 39endoplasmic reticulum lumencytosolplatelet dense tubular network lumenATPP2RX1 GNG4 GUCY1A3 STIM1 NOS2 Cyclic GMP-dependentprotein kinases(PKGs)ActivatedcGMP-dependentprotein kinase(PKGs)Phosphodiesterases, dual (cAMP, cGMP) activity GNAS2 Ca2+ PGI2 GNG13 GUCY1A2 P2RX4 GNGT1 GTP ITPR1 GNB5 LDL:LRP8:FGRCHEST GNG8 GNB4 GNG11 GNG3 ATP2B1-4ITPR1 CALM1PPP2CB GNB4 HeterotrimericG-protein Gs(inactive)PPP2CA GNG10 Guanylate cyclase:NONa+ APOB(28-4563) CHOL MRVI1 P2RX5 KCNMB4 ATP2A1-3GNG7 TAGs SLC8A3 ATP2B4 GNG12 GNG5 p-T180,Y182-MAPK14Ca2+GTPPPP2R5A CHEST BK channel,phosphorylatedPTGIR ATP2A2 GNGT1 P2RX6 NOS1,2,3GNG7 GNAS2 P2RX7 ADPAPOB(28-4563) LRP8 NADPHPGI2FGR GNB1 PRKG2 GNG12 PPiITPR3 Mg2+ STIM1 DimerPRKG2 PPP2R5D p-Y663,Y686-PECAM1(27-?)ATPATP2B1 Ca2+PL ORAI2 GNG3 p-Y663,Y686-PECAM1(27-?) KCNMA1 APOB(28-4563) GNAS2 IRAG:ITPR1NOS1 CHEST Na+NOGNG2 NO CHOL Ca2+ LRP8KCNMB2 L-CitGNGT2 PPP2CB GTP GNG10 GNB1 GUCY1A3 GUCY1B3 GNG7 PTGIR Mg2+ G alpha (s):GTPPTPN6GUCY1B2 GNAS1 GNB2 PPP2R1A GNGT2 CHOL GNG13 PPP2R5B KCNMB4 SLC8A1,2,3P2RX6 PGI2 TAGs ATP2A1 LRP8 GUCY1B3 GNGT1 KCNMB3 GNG10 NADP+PPP2R5D BK channelPRKG1-1 ORAI1 PAFAH2GDP CHEST PAFp-Y663,Y686-PECAM1(27-?) GNB5 GNG4 DAG-activatedTRPC3/6/7PPP2R1A P2RX1 GDPP2RX5 PLA2G4Ap-Y-LRP8 PECAM-1:SHP-2complexPECAM-1:SHP-1complexp-PECAM:PP2APPP2R5E P2RX receptorsTRPC7 O2p-S657,S670-MRVI1 LDL:LRP8ITPR2 cGMP GNG10 ATPGNG13 GNB1 PPP2R5C PL Prostacyclin:prostacyclin receptor:Gs (inactive)CHOL PP2ANa+ ORAI dimerP2RX3 Ca2+GNG12 GNG2 GNG11 cGMPphosphodiesterasesGNB5 GNB3 LDL:p-LRP8:FGRPTPN11 H2ODAG PL ATP2A3 GNB1 GUCY1B2 P2RX7 GNB3 KCNMB1 GNG5 GNB2 Ca2+ GUCY1B3 PTGIR:PGI2TAGs GNG5 Ca2+FGRPPP2R5E P2RX4 GNG3 GNG2 PTPN6 G-protein beta-gammacomplexORAI2 GNB3 GNGT2 Ca2+Na+Guanylate cyclase,solublePRKG1-1 GNGT2 GNG13 Mg2+ GNG12 p-S1195-KCNMA1 SLC8A2 PGI2 GNG2 GNB5 Phosphodiesterases, cyclic GMP-selective GNG8 PPP2CA GNAS1 GNB4 P2RX3 P2RX2 PPP2R1B ITPR1 ORAI1 FGR ATP2B3 MAPK14PL IP3Rtetramer:I(1,4,5)P3:4xCa2+GTPCH3COO-GNAS1 p-S505,S727-PLA2G4APPP2R1B NO:sGC:cinaciguatKCNMB2 GNAS2 GNGT1 KCNMB1 GNG8 Ca2+SLC8A1 NO:sGC:sGCstimulatorsGUCY1A2 GNG8 CRAC channelGNG7 Prostacyclin:prostacyclin receptor:G-protein Gs (active)ATP p-Y663,Y686-PECAM1(27-?) GUCY1B2 guanosine5'-monophosphateGNB2 PhosphorylatedIRAG:IP3 receptortype 1GUCY1A3 GNG3 L-ArgMg2+ ATP2B2 CationsI(1,4,5)P3 cGMPATPMg2+ PTPN11P2RX2 GNB3 GNB2 NOS3 TRPC3(1-848) PPP2R5C P2Xpurinoreceptors:ATPSRIH+ADPGNAS1 APOB(28-4563) ADPlyso-PAFSTIM1 GNG4 GUCY1A2 GDP TRPC6 PPP2R5A NO CationsLDLGNG11 PECAM1H+GNG5 GNG4 GNG11 KCNMB3 GNB4 TAGs PTGIR ADPPPP2R5B PTGIRATP


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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Pathway is converted from Reactome ID: 418346
Reactome version: 73
Reactome Author 
Reactome Author: Akkerman, Jan Willem N

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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


View all...
NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:456216 (ChEBI)
APOB(28-4563) ProteinP04114 (Uniprot-TrEMBL)
ATP MetaboliteCHEBI:30616 (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:30616 (ChEBI)

cGMP-dependent protein kinase

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.
CALM1ProteinP0DP23 (Uniprot-TrEMBL)
CH3COO-MetaboliteCHEBI:15366 (ChEBI)
CHEST MetaboliteCHEBI:17002 (ChEBI)
CHOL MetaboliteCHEBI:16113 (ChEBI)
CRAC channelComplexR-HSA-434679 (Reactome)
Ca2+ MetaboliteCHEBI:29108 (ChEBI)
Ca2+MetaboliteCHEBI:29108 (ChEBI)
CationsComplexR-ALL-426219 (Reactome)
CationsComplexR-ALL-426221 (Reactome)
Cyclic GMP-dependent

protein kinases

ComplexR-HSA-418379 (Reactome)
DAG MetaboliteCHEBI:17815 (ChEBI)
DAG-activated TRPC3/6/7ComplexR-HSA-426179 (Reactome)
FGR ProteinP09769 (Uniprot-TrEMBL)
FGRProteinP09769 (Uniprot-TrEMBL)
G alpha (s):GTPComplexR-HSA-164358 (Reactome)
G-protein beta-gamma complexComplexR-HSA-167434 (Reactome)
GDP MetaboliteCHEBI:17552 (ChEBI)
GDPMetaboliteCHEBI:17552 (ChEBI)
GNAS1 ProteinQ5JWF2 (Uniprot-TrEMBL)
GNAS2 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)
H2OMetaboliteCHEBI:15377 (ChEBI)

G-protein Gs

ComplexR-HSA-391179 (Reactome)
I(1,4,5)P3 MetaboliteCHEBI:16595 (ChEBI)
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:32682 (ChEBI)
L-CitMetaboliteCHEBI:16349 (ChEBI)
LDL:LRP8:FGRComplexR-HSA-8948036 (Reactome)
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)
NO:sGC:cinaciguatComplexR-HSA-9621123 (Reactome)
NO:sGC:sGC stimulatorsComplexR-HSA-9620466 (Reactome)
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)
ORAI dimerComplexR-HSA-8862646 (Reactome)
ORAI1 ProteinQ96D31 (Uniprot-TrEMBL)
ORAI2 ProteinQ96SN7 (Uniprot-TrEMBL)
P2RX receptorsComplexR-HSA-8861873 (Reactome)
P2RX1 ProteinP51575 (Uniprot-TrEMBL)
P2RX2 ProteinQ9UBL9 (Uniprot-TrEMBL)
P2RX3 ProteinP56373 (Uniprot-TrEMBL)
P2RX4 ProteinQ99571 (Uniprot-TrEMBL)
P2RX5 ProteinQ93086 (Uniprot-TrEMBL)
P2RX6 ProteinO15547 (Uniprot-TrEMBL)
P2RX7 ProteinQ99572 (Uniprot-TrEMBL)
P2X purinoreceptors: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.
PAFAH2ProteinQ99487 (Uniprot-TrEMBL)
PAFMetaboliteCHEBI:52450 (ChEBI)
PECAM-1:SHP-1 complexComplexR-HSA-210221 (Reactome)
PECAM-1:SHP-2 complexComplexR-HSA-210219 (Reactome)
PECAM1ProteinP16284 (Uniprot-TrEMBL)
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)
PTGIR:PGI2ComplexR-HSA-391929 (Reactome)
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)

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)
SRIProteinP30626 (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)
guanosine 5'-monophosphateMetaboliteCHEBI:17345 (ChEBI)
lyso-PAFMetaboliteCHEBI:91144 (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)
ADPArrowR-HSA-435244 (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)
ATPR-HSA-435244 (Reactome)

cGMP-dependent protein kinase

ArrowR-HSA-418451 (Reactome)
BK channel, phosphorylatedArrowR-HSA-418549 (Reactome)
BK channelR-HSA-418549 (Reactome)
CALM1TBarR-HSA-425661 (Reactome)
CH3COO-ArrowR-HSA-8869206 (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

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

protein kinases

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

protein kinases

mim-catalysisR-HSA-418549 (Reactome)
DAG-activated TRPC3/6/7mim-catalysisR-HSA-426223 (Reactome)
FGRR-HSA-8948034 (Reactome)
FGRmim-catalysisR-HSA-432148 (Reactome)
G alpha (s):GTPArrowR-HSA-392874 (Reactome)
G-protein beta-gamma complexArrowR-HSA-392874 (Reactome)
GDPArrowR-HSA-392870 (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)
H2OR-HSA-8869206 (Reactome)

G-protein Gs

R-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:LRP8:FGRArrowR-HSA-8948034 (Reactome)
LDL:LRP8:FGRR-HSA-432129 (Reactome)
LDL:LRP8:FGRmim-catalysisR-HSA-432129 (Reactome)
LDL:LRP8ArrowR-HSA-432121 (Reactome)
LDL:LRP8R-HSA-8948034 (Reactome)
LDL:p-LRP8:FGRArrowR-HSA-432129 (Reactome)
LDLArrowR-HSA-435244 (Reactome)
LDLR-HSA-432121 (Reactome)
LRP8R-HSA-432121 (Reactome)
MAPK14R-HSA-432148 (Reactome)
NADP+ArrowR-HSA-418436 (Reactome)
NADPHR-HSA-418436 (Reactome)
NO:sGC:cinaciguatArrowR-HSA-392152 (Reactome)
NO:sGC:sGC stimulatorsArrowR-HSA-392152 (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)
ORAI dimerR-HSA-434700 (Reactome)
P2RX receptorsR-HSA-419490 (Reactome)
P2X purinoreceptors:ATPArrowR-HSA-419490 (Reactome)
P2X purinoreceptors:ATPmim-catalysisR-HSA-139855 (Reactome)
PAFAH2mim-catalysisR-HSA-8869206 (Reactome)
PAFR-HSA-8869206 (Reactome)
PECAM-1:SHP-1 complexArrowR-HSA-210277 (Reactome)
PECAM-1:SHP-2 complexArrowR-HSA-210294 (Reactome)
PECAM1R-HSA-435244 (Reactome)
PGI2ArrowR-HSA-392874 (Reactome)
PGI2R-HSA-391942 (Reactome)
PLA2G4AR-HSA-428961 (Reactome)
PP2AR-HSA-432143 (Reactome)
PPiArrowR-HSA-392152 (Reactome)
PTGIR:PGI2ArrowR-HSA-391942 (Reactome)
PTGIR:PGI2R-HSA-392852 (Reactome)
PTGIRArrowR-HSA-392874 (Reactome)
PTGIRR-HSA-391942 (Reactome)
PTPN11R-HSA-210294 (Reactome)
PTPN6R-HSA-210277 (Reactome)

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-391942 (Reactome) Prostacyclin (PGI2) prevents formation of the platelet plug involved in primary hemostasis (a part of blood clot formation) and is an effective vasodilator. Binding to its receptor (IP, PTGIR) (Boie et al. 1994) allows coupling to and activation of the G protein alpha s subunit, which leads to activation of cAMP and increase in protein kinase A (PKA) activity (Schwaner et al. 1995).
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-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. Sarcolipin (SLN) can reversibly inhibit the activity of ATP2A1 by decreasing the apparent affinity of the ATPase for Ca2+ (Gorski et al. 2013) whereas activated Ca2+/CaM-dependent protein kinase II (CAMK2) and sorcin (SRI) can both stimulate ATP2A1-3 activity (Toyofuku et al. 1994, Matsumoto et al. 2005).
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) (Alderton WK et al. 2001). The three isozymes are regulated differentially. eNOS and nNOS, which are constitutively expressed in certain cells, are activated by he binding of calcium (Ca2+) and calmodulin (Alderton WK et al. 2001; Feng C 2012). iNOS is induced in response to immunostimulatory signals and once synthesized, iNos is constitutively active (Alderton WK et al. 2001; Aktan F 2004; Pautz A et al. 2010). 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) (Gicquel et al. 2015). All members of the family are thought to be functionally trimeric.
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, 2, 3 play a minor role during phase 2, since they begin to restore ion concentrations. The high concentration of intracellular calcium starts contraction of those cells, which is sustained in the plateau phase. 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.
In Rabbits, sorcin (SRI) activates SLC8A1, via the interaction of the respective Ca2+-binding domains (Zamparelli et al. 2010). Calmodulin (CALM1) binds to the cytoplasmic loop of NCX1 to negatively regulate exchange activity (Chou et al. 2015).
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 Orai 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 tyrosine phosphorylation and thereby activation of PECAM-1, which in turn leads to binding and stimulation of the Ser/Thr phosphatases PP1/PP2A which reduce the activity of p38MAPK by dephosphorylation.
R-HSA-8869206 (Reactome) Platelet-activating factor acetylhydrolase 2 (PAFAH2) (Rice et al. 1998) is an intracellular phospholipase A2 enzyme that inactivates the potent phospholipid mediator platelet-activating factor (PAF) and other structurally similar bioactive lipids produced in response to oxidative stress. PAFAH2 hydrolyses PAF at the sn-2 position, producing lyso-PAF and acetate (CH3COO-). Following oxidative stress, cytoplasmic PAFAH2 (present in homodimeric form) trafficks to the membranes of both the endoplasmic reticulum and Golgi apparatus; membrane localisation is critical for substrate acquisition and effective oxidative stress protection (Thevenin et al. 2011, Monillas et al. 2015). The enzyme that performs the last step in PAF synthesis is located on the outer leaf of the ER membrane. PAFAH2 ER localisation would allow it to access newly synthesized PAF, potentially serving as a control mechanism for PAF levels.
R-HSA-8948034 (Reactome) Tyrosine phosphorylation of LDL:LRP8 is mediated by the Src-family kinase FGR, based on a correlation of increased LRP8 phosphorylation in LDL-stimulated platelets and a transient increased co-precipitation of FGR and LRP8 upon LDL stimulation.
SLC8A1,2,3mim-catalysisR-HSA-425661 (Reactome)
SRIArrowR-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)
guanosine 5'-monophosphateArrowR-HSA-418456 (Reactome)
lyso-PAFArrowR-HSA-8869206 (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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