ADP-dependent platelet activation. Purvis et al use a computational model of the human platelet based on published kinetic data, electrochemical calculations, details of platelet ultrastructure, single cell analysis, and new data to predict temporal changes in intracellular Ca²⁺ levels, PI metabolites, and other ultrastructural parameters in response to ADP-dependent signaling through the purinergic Gq-coupled receptor, P2Y₁. In thrombus formation, initial adhesion of circulating resting platelets to the vessel wall triggers platelet activation and secretion of ADP that acts in an autocrine fashion to induce shape change, cytoskeletal rearrangements, elevation of Ca²⁺, and α_IIbβ₃-dependent platelet aggregation. ADP binding to P2Y₁ leads to down-stream activation of phospholipase C-β₂ (PLC-β), generation of DAG (that activates PKC) and inositol trisphosphate (IP₃), and elevation of cytosolic Ca²⁺ mediating platelet shape change and reversible platelet aggregation. Ca²⁺ levels are regulated by IP₃ receptor (IP₃R) channels, which release Ca²⁺ from the DTS and by a sarcoplasmic/endoplasmic reticulum Ca²⁺ ATPase (SERCA), which uptakes Ca²⁺. PKC phosphorylates/negatively regulates PLC-β. ADP binding P2Y₁₂ (Gi-coupled) leads to decreased adenyl cyclase/cAMP and consolidates α_IIbβ₃-dependent platelet aggregation (not shown).