Proposed mechanism for the regulation of Ca²⁺- and cAMP-mediated WPB exocytosis by RalGDS. (1) In unstimulated endothelial cells, RalGDS is complexed with β-arrestin in the cytoplasm, with the N-terminal part of RalGDS shielding off its catalytic GEF domain. (2) Thrombin stimulation leads to the release of Ca²⁺ in a PLC-dependent manner⁵⁹  and to the dissociation of the RalGDS-β-arrestin complex. (3) Ca²⁺/CaM complex interacts with the IQ-motif present in the N-terminus of RalGDS, inducing a conformational change that relieves RalGDS of autoinhibition of its exchange activity. (4) Simultaneously, RalGDS translocates to the plasma membrane in a RBD-dependent manner by association of its RBD domain with a membrane-tethered active GTPase. (5) Membrane-associated active RalGDS activates Ral, which mediates release of WPBs through the coordination of the exocyst complex and PLD-induced fusion of vesicular and plasma membrane. (6) Triggering of the β2-adrenergic receptor leads to a rise in intracellular cAMP through the action of adenylate cyclase (AC). (7) cAMP-activated protein kinase A phosphorylates RalGDS, causing its translocation and/or partial activation, eventually leading to Ral activation and WPB exocytosis.