Regulator of G-protein signaling 3 (RGS3) enhances the intrinsic rate at which Gαi and Gαq hydrolyze GTP to GDP, thereby limiting the duration in which GTP-Gαi and GTP-Gαq can activate effectors. Since GDP-Gα1 subunits rapidly combine with free Gβγ subunits to reform inactive heterotrimeric G-proteins, RGS3 and other RGS proteins may also reduce the amount of Gβ subunits available for effector interactions. Although RGS6, RGS7, and RGS11 bind Gβ5 in the absence of a Gγ subunit, RGS proteins are not known to directly influence Gβγ signaling. Here we show that RGS3 binds Gβ1γ2 subunits and limits their ability to trigger the production of inositol phosphates and the activation of Akt and mitogen-activated protein kinase. Co-expression of RGS3 with Gβ1γ2 inhibits Gβ1γ 2-induced inositol phosphate production and Akt activation in COS-7 cells and mitogen-activated protein kinase activation in HEK 293 cells. The inhibition of Gβ1γ2 signaling does not require an intact RGS domain but depends upon two regions in RGS3 located between acids 313 and 390 and between 391 and 458. Several other RGS proteins do not affect Gβ1γ2 signaling in these assays. Consistent with the in vivo results, RGS3 inhibits Gβγ-mediated activation of phospholipase Cβ in vitro. Thus, RGS3 may limit Gβγ signaling not only by virtue of its GTPase-activating protein activity for Gα subunits, but also by directly interfering with the activation of effectors.
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Shi, C. S., Lee, S. B., Sinnarajah, S., Dessauer, C. W., Rhee, S. G., & Kehrl, J. H. (2001). Regulator of G-protein Signaling 3 (RGS3) Inhibits Gβ 1,γ2-induced Inositol Phosphate Production, Mitogen-activated Protein Kinase Activation, and Akt Activation. Journal of Biological Chemistry, 276(26), 24293–24300. https://doi.org/10.1074/jbc.M100089200