Fig. 10. Schemes of the two signaling cascades activated by anandamide in endothelial cells. (A) Anandamide-induced Ca²⁺ signaling under conditions of unclustered integrins originates from CB₁R that is linked to β1 integrin and stimulates Syk via G_i/o, subsequently resulting in the activation of NFB, Erk1 and Erk2. Additionally, Syk inhibits PI3K and, thus, the downstream signaling of the GPR55 is prevented. (B) Once integrins are clustered, CB₁R uncouples from β1 integrin and, thus, no negative feedback on PI3K via Syk occurs. Consequently, GPR55-initiated signaling becomes promoted, resulting in the activation of a PI3K-Bmx-PLC cascade that triggers in the production of IP₃ and subsequent intracellular Ca²⁺ mobilization, yielding activation of NFAT, Erk1 and Erk2. Based on the data presented, involvement of G_q/s in GPR55-triggered signaling cannot be not confirmed or excluded at this stage. Abbreviations: 1β3, 1β3 integrin; v5, v5 integrin; Bmx/Etk, bone marrow kinase, X-linked/epithelial and endothelial tyrosine kinase; CB₁R, cannabinoid 1 receptor; ER, endoplasmic reticulum; Erk1/2, extracellular signal regulated kinases 1 and 2; GPR55, G-protein-coupled receptor 55 (e-aR, `atypical' endothelial anandamide receptor); IP₃, Ins(1,4,5)P₃; G_i, G_i protein; G_q, G_q (G₁₃) protein; NFAT, nuclear factor of activated T-cells; NFB, nuclear factor B; p50, nuclear factor B p50; p65, nuclear factor B, subunit 3; PI3K, phosphoinositide 3-kinase; PLC, phospholipase C; Syk, spleen tyrosine kinase; Tk, tyrosine kinase.