Figure 1.

Key signaling pathways in platelets linked to (reversible) integrin activation αIIbβ3 and platelet aggregation. For explanations, see text. In short, the IP receptor for prostacyclin inhibits platelets via adenylyl cyclase (AC), while gaseous nitric oxide inhibits platelets via guanylate cyclase (GC); the formed cAMP and cGMP activate protein kinase A (PKA) and protein kinase G (PKG), respectively. As platelet adhesion receptors, integrin and GPIb-V-IX interact with fibrinogen, fibrin and von Willebrand factor (VWF). The purinoceptors P2Y₁₂ and P2Y₁ operate after autocrine release of ADP; P2Y₁₂ acts via the G protein Giα, inhibiting AC but stimulating phosphoinositide 3-kinase (PI3K). On the other hand, P2Y₁ signals via Gqα which stimulates phospholipase C (PLC), causing Ca²⁺ release and activation of protein kinase C (PKC). As a strong platelet agonist, thrombin also activates Gqα-coupled receptors, namely PAR1 and PAR4. The collagen receptor GPVI activates a protein tyrosine kinase pathway involving Syk and Btk, leading to downstream activation of PLC and PI3K isoforms, the latter stimulating Akt protein kinase. The signaling toward activation of αIIbβ3 furthermore involves the small GTPase-regulating proteins CalDAG-GEFI (calcium and diacylglycerol regulated guanine nucleotide exchange factor I), Ras3a and Rap1b. The cytoskeleton-linked signaling is completed by kindlin and talin isoforms. Black arrows show relative strength of pathways to integrin activation; red arrows connected to blue-boxed proteins represent inhibitory pathways.