Signal amplification (Homo sapiens)

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11215814, 1555211, 12912, 13599, 1057634endoplasmic reticulum lumencytosolGDPG-protein beta-gamma complexADPcPLA2ADP:P2Y purinoceptor 1:G-protein Gq (inactive)Active SRC (p-Y419)Heterotrimeric G-protein Gi (inactive)ATPP2RY12ADPATPADP:P2Y purinoceptor 1GDPADP:P2Y prurinoceptor 1:G-protein Gq (active)ADP:P2Y purinoceptor 12:G-protein Gi (active)SRCHeterotrimeric G-protein G13 (inactive)GTPGDPG-protein alpha (i): GTPADPTP receptor:Thromboxane A2TP receptor:Thromboxane A2:G-protein G13 (inactive)phospho-cPLA2GDPPhospho-MAP kinase p38 alphaADPG-protein alpha (13):GTPGTPP2RY1Thromboxane A2MAP kinase p38 alphaGTPTP receptor:Thromboxane A2:G-protein Gq (active)TP receptor:Thromboxane A2:G-protein G13 (active)ADP:P2Y purinoceptor 12:G-protein Gi (inactive)TP receptor:Thromboxane A2:G-protein Gq (inactive)Heterotrimeric G-protein Gq/11 (inactive)G-protein alpha (q/11): GTPADP:P2Y purinoceptor 12TP receptorGTP


Description

In the initial response to injury, platelets adhere to damaged blood vessels, responding to the exposure of collagen from the vascular epithelium. Once adhered they degranulate, releasing stored secondary agents such as ADP and ATP, and synthesized thromboxane A2. These amplify the response, activating and recruiting further platelets to the area and promoting platelet aggregation. Adenosine nucleotides secreted following platelet activation signal through P2 purinergic receptors on the platelet membrane. ADP activates P2Y1 and P2Y12 while ATP activates the ionotropic P2X1 receptor (Kunapuli et al. 2003). Activation of these receptors initiates a complex signaling cascade that ultimately results in platelet activation and thrombus formation (Kahner et al. 2006). ADP stimulation of P2Y1 and P2Y12 involves signaling via both the alpha and gamma:beta components of the heterotrimeric G-protein (Hirsch et al. 2001, 2006).

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Bibliography

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  1. Hardy AR, Jones ML, Mundell SJ, Poole AW.; ''Reciprocal cross-talk between P2Y1 and P2Y12 receptors at the level of calcium signaling in human platelets.''; PubMed Europe PMC Scholia
  2. Léon C, Vial C, Cazenave JP, Gachet C.; ''Cloning and sequencing of a human cDNA encoding endothelial P2Y1 purinoceptor.''; PubMed Europe PMC Scholia
  3. Schachter JB, Li Q, Boyer JL, Nicholas RA, Harden TK.; ''Second messenger cascade specificity and pharmacological selectivity of the human P2Y1-purinoceptor.''; PubMed Europe PMC Scholia
  4. Kramer RM, Roberts EF, Um SL, Börsch-Haubold AG, Watson SP, Fisher MJ, Jakubowski JA.; ''p38 mitogen-activated protein kinase phosphorylates cytosolic phospholipase A2 (cPLA2) in thrombin-stimulated platelets. Evidence that proline-directed phosphorylation is not required for mobilization of arachidonic acid by cPLA2.''; PubMed Europe PMC Scholia
  5. Chou KC.; ''Coupling interaction between thromboxane A2 receptor and alpha-13 subunit of guanine nucleotide-binding protein.''; PubMed Europe PMC Scholia
  6. Lambert NA.; ''Dissociation of heterotrimeric g proteins in cells.''; PubMed Europe PMC Scholia
  7. Davì G, Patrono C.; ''Platelet activation and atherothrombosis.''; PubMed Europe PMC Scholia
  8. Kinsella BT, O'Mahony DJ, Fitzgerald GA.; ''The human thromboxane A2 receptor alpha isoform (TP alpha) functionally couples to the G proteins Gq and G11 in vivo and is activated by the isoprostane 8-epi prostaglandin F2 alpha.''; PubMed Europe PMC Scholia
  9. Dangelmaier C, Jin J, Daniel JL, Smith JB, Kunapuli SP.; ''The P2Y1 receptor mediates ADP-induced p38 kinase-activating factor generation in human platelets.''; PubMed Europe PMC Scholia
  10. Hirata M, Hayashi Y, Ushikubi F, Yokota Y, Kageyama R, Nakanishi S, Narumiya S.; ''Cloning and expression of cDNA for a human thromboxane A2 receptor.''; PubMed Europe PMC Scholia
  11. Shenker A, Goldsmith P, Unson CG, Spiegel AM.; ''The G protein coupled to the thromboxane A2 receptor in human platelets is a member of the novel Gq family.''; PubMed Europe PMC Scholia
  12. Hollopeter G, Jantzen HM, Vincent D, Li G, England L, Ramakrishnan V, Yang RB, Nurden P, Nurden A, Julius D, Conley PB.; ''Identification of the platelet ADP receptor targeted by antithrombotic drugs.''; PubMed Europe PMC Scholia
  13. Bodor ET, Waldo GL, Hooks SB, Corbitt J, Boyer JL, Harden TK.; ''Purification and functional reconstitution of the human P2Y12 receptor.''; PubMed Europe PMC Scholia
  14. Ohlmann P, Laugwitz KL, Nürnberg B, Spicher K, Schultz G, Cazenave JP, Gachet C.; ''The human platelet ADP receptor activates Gi2 proteins.''; PubMed Europe PMC Scholia
  15. Schachter JB, Sromek SM, Nicholas RA, Harden TK.; ''HEK293 human embryonic kidney cells endogenously express the P2Y1 and P2Y2 receptors.''; PubMed Europe PMC Scholia
  16. Zhang L, DiLizio C, Kim D, Smyth EM, Manning DR.; ''The G12 family of G proteins as a reporter of thromboxane A2 receptor activity.''; PubMed Europe PMC Scholia
  17. Reid HM, Wikström K, Kavanagh DJ, Mulvaney EP, Kinsella BT.; ''Interaction of angio-associated migratory cell protein with the TPα and TPβ isoforms of the human thromboxane A₂ receptor.''; PubMed Europe PMC Scholia
  18. Waldo GL, Harden TK.; ''Agonist binding and Gq-stimulating activities of the purified human P2Y1 receptor.''; PubMed Europe PMC Scholia
  19. Ding Z, Kim S, Dorsam RT, Jin J, Kunapuli SP.; ''Inactivation of the human P2Y12 receptor by thiol reagents requires interaction with both extracellular cysteine residues, Cys17 and Cys270.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
114772view16:26, 25 January 2021ReactomeTeamReactome version 75
113216view11:28, 2 November 2020ReactomeTeamReactome version 74
112440view15:38, 9 October 2020ReactomeTeamReactome version 73
101345view11:23, 1 November 2018ReactomeTeamreactome version 66
100883view20:57, 31 October 2018ReactomeTeamreactome version 65
100424view19:31, 31 October 2018ReactomeTeamreactome version 64
99973view16:15, 31 October 2018ReactomeTeamreactome version 63
99528view14:51, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99167view12:42, 31 October 2018ReactomeTeamreactome version 62
93937view13:46, 16 August 2017ReactomeTeamreactome version 61
93526view11:26, 9 August 2017ReactomeTeamreactome version 61
86625view09:22, 11 July 2016ReactomeTeamreactome version 56
83050view09:47, 18 November 2015ReactomeTeamVersion54
81353view12:52, 21 August 2015ReactomeTeamVersion53
76822view08:04, 17 July 2014ReactomeTeamFixed remaining interactions
76526view11:45, 16 July 2014ReactomeTeamFixed remaining interactions
75859view09:51, 11 June 2014ReactomeTeamRe-fixing comment source
75559view10:35, 10 June 2014ReactomeTeamReactome 48 Update
74914view13:44, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74558view08:35, 30 April 2014ReactomeTeamReactome46
45229view17:42, 7 October 2011KhanspersOntology Term : 'G protein mediated signaling pathway' added !
45228view17:41, 7 October 2011KhanspersOntology Term : 'platelet aggregation pathway' added !
45227view17:40, 7 October 2011KhanspersOntology Term : 'platelet' added !
42124view21:58, 4 March 2011MaintBotAutomatic update
39934view05:57, 21 January 2011MaintBotNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ADP Metabolite16761 (ChEBI)
ADP:P2Y

prurinoceptor 1: G-protein Gq (active)

ComplexREACT_20825 (Reactome)
ADP:P2Y purinoceptor

12

ComplexREACT_20705 (Reactome)
ADP:P2Y purinoceptor

12:G-protein Gi (active)

ComplexREACT_20967 (Reactome)
ADP:P2Y purinoceptor

12:G-protein Gi (inactive)

ComplexREACT_21024 (Reactome)
ADP:P2Y purinoceptor

1:G-protein Gq (inactive)

ComplexREACT_21114 (Reactome)
ADP:P2Y purinoceptor 1 ComplexREACT_21127 (Reactome)
ATP Metabolite15422 (ChEBI)
Active SRC (p-Y419) ProteinP12931-1 (UniProt)
G-protein alpha

(13):GTP

ComplexREACT_18118 (Reactome)
G-protein alpha

(i): GTP

ComplexREACT_19580 (Reactome)
G-protein alpha

(q/11): GTP

ComplexREACT_5863 (Reactome)
G-protein beta-

gamma complex

ComplexREACT_15674 (Reactome)
GDP Metabolite17552 (ChEBI)
GTP Metabolite15996 (ChEBI)
Heterotrimeric G-

protein G13 (inactive)

ComplexREACT_17830 (Reactome)
Heterotrimeric G-

protein Gi (inactive)

ComplexREACT_20935 (Reactome)
Heterotrimeric G-

protein Gq/11 (inactive)

ComplexREACT_5130 (Reactome)
MAP kinase p38

alpha

ProteinQ16539 (UniProt)
P2RY1 ProteinP47900 (UniProt)
P2RY12 ProteinQ9H244 (UniProt)
Phospho-MAP kinase

p38 alpha

ProteinQ16539 (UniProt)
SRC ProteinP12931-1 (UniProt)
TP receptor ProteinP21731 (UniProt)
TP receptor:

Thromboxane A2

ComplexREACT_18599 (Reactome)
TP receptor:

Thromboxane A2: G-protein G13 (active)

ComplexREACT_20781 (Reactome)
TP receptor:

Thromboxane A2: G-protein Gq (active)

ComplexREACT_20944 (Reactome)
TP receptor:

Thromboxane A2: G-protein Gq (inactive)

ComplexREACT_20867 (Reactome)
TP receptor:

Thromboxane A2:G- protein G13 (inactive)

ComplexREACT_20823 (Reactome)
Thromboxane A2 Metabolite15627 (ChEBI)
cPLA2 ProteinP47712 (UniProt)
phospho-cPLA2 ProteinP47712 (UniProt)

Annotated Interactions

No annotated interactions

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