The RGS handoff in platelets. RGS proteins serve to limit platelet activation by limiting the duration of G protein–dependent signaling, illustrated here for G_q-mediated activation of phospholipase C leading to the production of IP₃ and diacylglycerol from phosphatidylinositol-4,5-bisphosphate (PIP₂), the second messengers that increase the Ca⁺⁺ concentration in platelets and activate protein kinase C. This model suggests that the amount of free RGS18 (and by implication RGS10) in resting platelets is determined in part by binding to spinophilin and by protein kinase A (PKA)– or protein kinase G (PKG, not shown)–mediated phosphorylation of Ser216. In activated platelets, release of RGS18 from spinophilin/SHP-1 complex promotes inhibition of signaling, but subsequent phosphorylation of Ser49 and Ser218 allows sequestration of the RGS protein by a 14-3-3γ unless Ser216 phosphorylation is present. Not all aspects of this model have been established, but it provides testable hypotheses for tightly regulating the availability of free RGS proteins in platelets. AC indicates adenylyl cyclase; NO, nitric oxide; PGI₂, prostaglandin I₂; SFK, Src family kinase; PKC, protein kinase C; and TxA₂, thromboxane A₂. The authors thank Dr Timothy J. Stalker (Perelman School of Medicine, University of Pennsylvania) for assistance with the figure.