Schematic representation of the role of GIRK channels in ADP-induced TXA₂ generation. ADP induces platelet aggregation by activating the P2Y₁ and P2Y₁₂ receptors. P2Y₁₂ receptor stimulation causes the release of the βγ dimers from the Gα_i subunit, which activates the GIRK channels by binding to their cytosolic regions. Costimulation of P2Y₁ and P2Y₁₂ receptors is important for ADP-induced cPLA₂ phosphorylation on the serine 505 residue, AA release, and TXA₂ generation. Selective stimulation of the P2Y₁₂ receptor leads to Src tyrosine kinase activation, which is inhibited by GIRK channel blockade. Activation of both GIRK channels and Src family of tyrosine kinases, following P2Y₁₂ receptor stimulation, is essential for ADP-induced cPLA₂ phosphorylation and for TXA₂ generation. SCH23390 and U50488H are the 2 structurally distinct GIRK channel blockers that have been used in our study.