Figure 2.

Model of P2Y₂ receptor signaling to G_q proteins, ion channels, and growth factor receptors. Stimulation of the P2Y₂ receptor with ATP or UTP causes Gα_q-dependent activation of phospholipase C-β (PLCβ) resulting in the hydrolysis of PtdIns(4,5)P₂ to produce the second messengers Ins(1,4,5)P₃ (IP₃), which mobilizes intracellular Ca²⁺, and diacylglycerol (DAG), which activates protein kinase C (PKC).¹⁰ Downstream signaling molecules include calmodulin (CaM), calmodulin-dependent kinase (CaMK), nitric oxide synthase (NOS), nitric oxide (NO), guanylyl cyclase (GC), cyclic GMP (cGMP), protein kinase G (PKG), cytosolic phospholipase A2 (cPLA₂), arachidonic acid (AA), and prostaglandin E2 (PGE2). The P2Y₂ receptor transactivates several growth factor receptors, including EGFRs, PDGFR, and VEGFR-2, through Src-dependent activation of the focal adhesion-related tyrosine kinase (Pyk2), which phosphorylates growth factor receptors and leads to activation of serine/threonine kinases (e.g., ERK1/2, JNK, p38, LIMK1, and p90RSK) and transcription factors (e.g., CREB, NF-kb, ELK-1, c-FOS, and c-JUN) that regulate genes involved in inflammation, apoptosis, cell differentiation, and so on.¹⁰ Src, which binds to Src homology 3 (SH3) domains in the P2Y₂ receptor,¹²⁴ also is involved in the activation of the monomeric G protein (Rac1) and p21-activated serine kinase (PAK) as well as phosphatidylinositol 3-kinase (PI3K) and protein kinase B (Akt). The P2Y₂ receptor also transactivates EGFRs by activating metalloproteases (ADAM10 and ADAM17), causing the cleavage and release of EGFR ligands, neuregulin and heparin-binding EGF (HB-EGF), which directly activate EGFRs.^126,127