PI3-kinase is essential for ADP-stimulated integrin αIIbβ3-mediated platelet calcium oscillation, implications for P2Y receptor pathways in integrin αIIbβ3-initiated signaling cross-talks

Abstract

Phosphatidylinositol 3-kinase (PI3K) pathway is important for platelet activation. Recent studies showed that PI3K and oscillative calcium could cross talk to each other and positively regulate integrin alpha (IIb)beta3-mediated outside-in signaling. However, the mechanism of this feedback regulation remains to be further characterized. Here we found that treatments of both PI3K inhibitor wortmannin and P2Y1 inhibitor A3P5P could inhibit granular secretion in platelets. Additionally, when RGD-substrate adherent platelets were treated with the ADP scavenger apyrase to deplete the granular-released ADP, their attachments in engaging with substrates became looser and the frequency of calcium oscillation decreased. Since it is known that ADP stimulates the PI3K and calcium signal primarily through P2Y12 and P2Y1 receptors respectively, our data indicated that integrin alpha(IIb)beta3 downstream PI3K and calcium activation might be not completely coupled to integrin associated signaling complex, but in part through feedback stimulation by granular released ADP. Our data indicates the important roles of PI3K and granular released ADP in coordinating the feedback regulations in integrin alpha(IIb)beta3-mediated platelet activation.

Blood cells: an historical account of the roles of purinergic signalling

“…Platelet integrin α IIb β 3 plays a crucial role in platelet aggregation, and it was claimed that phosphatidylinositol 3-kinase is essential for ADP-stimulated α IIb β 3 -mediated platelet activation and calcium oscillations [250]. Continuous interaction between ADP and P2Y 12 receptors is critical for the maintenance of α IIb β 3 activation [251][252][253].…”

Identification, Characterization, and Epitope Mapping of Human Monoclonal Antibody J19 That Specifically Recognizes Activated Integrin α4β7

“…DTT has been shown to activate integrin in a number of systems (38,39). ADP was reported to induce integrin activation through inside-out signaling by activating PI3K pathway (41). To further study the binding specificity of J19 IgG to ␣ 4 ␤ 7 activated by different stimuli, K562 cells stably expressing ␣ 4 ␤ 7 were treated with Mn 2ϩ , DTT, or ADP and then followed by staining with 5 g/ml J19 IgG.…”

Soluble P-selectin rescues viper venom–induced mortality through anti-inflammatory properties and PSGL-1 pathway-mediated correction of hemostasis

“…These snakes eat small animals and hunt by striking and envenoming to immobilize and kill prey4. Their venom comprises various coagulation-disrupting proteins15, which can cause functional alterations in coagulation factors and platelets5678910111213141516171819; thus, snakebites by vipers usually lead to inflammation and hemorrhage12520212223. Antivenom injection is a major treatment for venomous snakebites, but little high-quality data is available to support its effectiveness, particularly in cases with venom-elicited coagulopathy152425.…”