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.
Antl M, von Brühl ML, Eiglsperger C, Werner M, Konrad I, Kocher T, Wilm M, Hofmann F, Massberg S, Schlossmann J.; ''IRAG mediates NO/cGMP-dependent inhibition of platelet aggregation and thrombus formation.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Hua CT, Gamble JR, Vadas MA, Jackson DE.; ''Recruitment and activation of SHP-1 protein-tyrosine phosphatase by human platelet endothelial cell adhesion molecule-1 (PECAM-1). Identification of immunoreceptor tyrosine-based inhibitory motif-like binding motifs and substrates.''; PubMedEurope PMCScholia
Thévenin AF, Monillas ES, Winget JM, Czymmek K, Bahnson BJ.; ''Trafficking of platelet-activating factor acetylhydrolase type II in response to oxidative stress.''; PubMedEurope PMCScholia
Zhang L, Wu J, Ruan KH.; ''Solution structure of the first intracellular loop of prostacyclin receptor and implication of its interaction with the C-terminal segment of G alpha s protein.''; PubMedEurope PMCScholia
Bokkala S, el-Daher SS, Kakkar VV, Wuytack F, Authi KS.; ''Localization and identification of Ca2+ATPases in highly purified human platelet plasma and intracellular membranes. Evidence that the monoclonal antibody PL/IM 430 recognizes the SERCA 3 Ca2+ATPase in human platelets.''; PubMedEurope PMCScholia
Lambert NA.; ''Dissociation of heterotrimeric g proteins in cells.''; PubMedEurope PMCScholia
Loughney K, Martins TJ, Harris EA, Sadhu K, Hicks JB, Sonnenburg WK, Beavo JA, Ferguson K.; ''Isolation and characterization of cDNAs corresponding to two human calcium, calmodulin-regulated, 3',5'-cyclic nucleotide phosphodiesterases.''; PubMedEurope PMCScholia
Fumagalli L, Zhang H, Baruzzi A, Lowell CA, Berton G.; ''The Src family kinases Hck and Fgr regulate neutrophil responses to N-formyl-methionyl-leucyl-phenylalanine.''; PubMedEurope PMCScholia
Gabellini N, Bortoluzzi S, Danieli GA, Carafoli E.; ''The human SLC8A3 gene and the tissue-specific Na+/Ca2+ exchanger 3 isoforms.''; PubMedEurope PMCScholia
Park CY, Hoover PJ, Mullins FM, Bachhawat P, Covington ED, Raunser S, Walz T, Garcia KC, Dolmetsch RE, Lewis RS.; ''STIM1 clusters and activates CRAC channels via direct binding of a cytosolic domain to Orai1.''; PubMedEurope PMCScholia
Komuro I, Wenninger KE, Philipson KD, Izumo S.; ''Molecular cloning and characterization of the human cardiac Na+/Ca2+ exchanger cDNA.''; PubMedEurope PMCScholia
Zhu X, Jiang M, Peyton M, Boulay G, Hurst R, Stefani E, Birnbaumer L.; ''trp, a novel mammalian gene family essential for agonist-activated capacitative Ca2+ entry.''; PubMedEurope PMCScholia
Hofmann T, Obukhov AG, Schaefer M, Harteneck C, Gudermann T, Schultz G.; ''Direct activation of human TRPC6 and TRPC3 channels by diacylglycerol.''; PubMedEurope PMCScholia
Relou IA, Gorter G, Ferreira IA, van Rijn HJ, Akkerman JW.; ''Platelet endothelial cell adhesion molecule-1 (PECAM-1) inhibits low density lipoprotein-induced signaling in platelets.''; PubMedEurope PMCScholia
Korporaal SJ, Relou IA, van Eck M, Strasser V, Bezemer M, Gorter G, van Berkel TJ, Nimpf J, Akkerman JW, Lenting PJ.; ''Binding of low density lipoprotein to platelet apolipoprotein E receptor 2' results in phosphorylation of p38MAPK.''; PubMedEurope PMCScholia
DeHaven WI, Smyth JT, Boyles RR, Putney JW.; ''Calcium inhibition and calcium potentiation of Orai1, Orai2, and Orai3 calcium release-activated calcium channels.''; PubMedEurope PMCScholia
Stitham J, Stojanovic A, Merenick BL, O'Hara KA, Hwa J.; ''The unique ligand-binding pocket for the human prostacyclin receptor. Site-directed mutagenesis and molecular modeling.''; PubMedEurope PMCScholia
Ransnäs LA, Insel PA.; ''Subunit dissociation is the mechanism for hormonal activation of the Gs protein in native membranes.''; PubMedEurope PMCScholia
Armstrong RA, Lawrence RA, Jones RL, Wilson NH, Collier A.; ''Functional and ligand binding studies suggest heterogeneity of platelet prostacyclin receptors.''; PubMedEurope PMCScholia
Sun B, Li J, Okahara K, Kambayashi J.; ''P2X1 purinoceptor in human platelets. Molecular cloning and functional characterization after heterologous expression.''; PubMedEurope PMCScholia
Becker BF, Heindl B, Kupatt C, Zahler S.; ''Endothelial function and hemostasis.''; PubMedEurope PMCScholia
Zschauer A, van Breemen C, Bühler FR, Nelson MT.; ''Calcium channels in thrombin-activated human platelet membrane.''; PubMedEurope PMCScholia
Vial C, Pitt SJ, Roberts J, Rolf MG, Mahaut-Smith MP, Evans RJ.; ''Lack of evidence for functional ADP-activated human P2X1 receptors supports a role for ATP during hemostasis and thrombosis.''; PubMedEurope PMCScholia
Li Z, Matsuoka S, Hryshko LV, Nicoll DA, Bersohn MM, Burke EP, Lifton RP, Philipson KD.; ''Cloning of the NCX2 isoform of the plasma membrane Na(+)-Ca2+ exchanger.''; PubMedEurope PMCScholia
Riccio A, Mattei C, Kelsell RE, Medhurst AD, Calver AR, Randall AD, Davis JB, Benham CD, Pangalos MN.; ''Cloning and functional expression of human short TRP7, a candidate protein for store-operated Ca2+ influx.''; PubMedEurope PMCScholia
Spamer C, Heilmann C, Gerok W.; ''Ca2+-activated ATPase in microsomes from human liver.''; PubMedEurope PMCScholia
Mócsai A, Jakus Z, Vántus T, Berton G, Lowell CA, Ligeti E.; ''Kinase pathways in chemoattractant-induced degranulation of neutrophils: the role of p38 mitogen-activated protein kinase activated by Src family kinases.''; PubMedEurope PMCScholia
Jackson DE, Ward CM, Wang R, Newman PJ.; ''The protein-tyrosine phosphatase SHP-2 binds platelet/endothelial cell adhesion molecule-1 (PECAM-1) and forms a distinct signaling complex during platelet aggregation. Evidence for a mechanistic link between PECAM-1- and integrin-mediated cellular signaling.''; PubMedEurope PMCScholia
Monillas ES, Caplan JL, Thévenin AF, Bahnson BJ.; ''Oligomeric state regulated trafficking of human platelet-activating factor acetylhydrolase type-II.''; PubMedEurope PMCScholia
Katsuyama M, Sugimoto Y, Namba T, Irie A, Negishi M, Narumiya S, Ichikawa A.; ''Cloning and expression of a cDNA for the human prostacyclin receptor.''; PubMedEurope PMCScholia
Verma AK, Filoteo AG, Stanford DR, Wieben ED, Penniston JT, Strehler EE, Fischer R, Heim R, Vogel G, Mathews S.; ''Complete primary structure of a human plasma membrane Ca2+ pump.''; PubMedEurope PMCScholia
Rice SQ, Southan C, Boyd HF, Terrett JA, MacPhee CH, Moores K, Gloger IS, Tew DG.; ''Expression, purification and characterization of a human serine-dependent phospholipase A2 with high specificity for oxidized phospholipids and platelet activating factor.''; PubMedEurope PMCScholia
Muik M, Frischauf I, Derler I, Fahrner M, Bergsmann J, Eder P, Schindl R, Hesch C, Polzinger B, Fritsch R, Kahr H, Madl J, Gruber H, Groschner K, Romanin C.; ''Dynamic coupling of the putative coiled-coil domain of ORAI1 with STIM1 mediates ORAI1 channel activation.''; PubMedEurope PMCScholia
Chou AC, Ju YT, Pan CY.; ''Calmodulin Interacts with the Sodium/Calcium Exchanger NCX1 to Regulate Activity.''; PubMedEurope PMCScholia
Luik RM, Wang B, Prakriya M, Wu MM, Lewis RS.; ''Oligomerization of STIM1 couples ER calcium depletion to CRAC channel activation.''; PubMedEurope PMCScholia
Derbyshire ER, Marletta MA.; ''Biochemistry of soluble guanylate cyclase.''; PubMedEurope PMCScholia
Boie Y, Rushmore TH, Darmon-Goodwin A, Grygorczyk R, Slipetz DM, Metters KM, Abramovitz M.; ''Cloning and expression of a cDNA for the human prostanoid IP receptor.''; PubMedEurope PMCScholia
Zamparelli C, Macquaide N, Colotti G, Verzili D, Seidler T, Smith GL, Chiancone E.; ''Activation of the cardiac Na(+)-Ca(2+) exchanger by sorcin via the interaction of the respective Ca(2+)-binding domains.''; PubMedEurope PMCScholia
Schwaner I, Offermanns S, Spicher K, Seifert R, Schultz G.; ''Differential activation of Gi and Gs proteins by E- and I-type prostaglandins in membranes from the human erythroleukaemia cell line, HEL.''; PubMedEurope PMCScholia
Mahaut-Smith MP, Sage SO, Rink TJ.; ''Receptor-activated single channels in intact human platelets.''; PubMedEurope PMCScholia
Schatzmann HJ.; ''ATP-dependent Ca++-extrusion from human red cells.''; PubMedEurope PMCScholia
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 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.
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.
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.
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.
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.
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.
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.
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).
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.
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.
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.
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).
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.
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).
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).
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.
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.
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.
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.
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.
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).
TRP channels are non-selectively permeable to cations, allowing enty into the cell via concentration gradients. All mammalian TRPCs require PLC for activation.
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).
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.
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.
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.
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.
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.
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.
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.
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.
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cGMP-dependent protein kinase
(PKGs)protein kinases
(PKGs)G-protein Gs
(inactive)IRAG:IP3 receptor
type 1Annotated Interactions
cGMP-dependent protein kinase
(PKGs)protein kinases
(PKGs)protein kinases
(PKGs)protein kinases
(PKGs)G-protein Gs
(inactive)IRAG:IP3 receptor
type 1Functionally the IP3 receptor is believed to be tetrameric, with results indicating that the tetramer is composed of 2 pairs of protein isoforms.
PDE2, 3 and 5 are expressed in platelets.
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).
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).