Model of RGS18 regulation during platelet activation and inhibition. RGS18 is a GTPase-activating protein of Gq and is constitutively bound to 14-3-3 via phosphorylated S218. Platelet activation by thrombin leads to the phosphorylation of S49 on RGS18 (pS49) by an unknown protein kinase. This results in increased RGS18 affinity to 14-3-3. RGS18 bound to 14-3-3 is a less efficient GTPase-activator of Gq, resulting in higher levels of active Gq-GTP, which stimulates release of calcium ions from intracellular stores (Ca²⁺-release), leading to platelet aggregation. Therefore, Gq signaling is facilitated during platelet activation. PGI₂ and NO are released from endothelial cells and stimulate the activation of cAMP- and cGMP-dependent protein kinases (PKA/G). PKA and PKG phosphorylate RGS18 on S216 (pS216), leading to the detachment of 14-3-3 from RGS18. Detachment of 14-3-3 causes RGS18 to turn off Gq signaling more efficiently, resulting in decreased intracellular Ca²⁺ release and platelet inhibition. In this way, RGS18 is able to integrate activating and inhibitory signaling in platelets at the level of Gq.