Regulator of G-protein signaling 3 (RGS3) inhibits Gβ1γ2-induced inositol phosphate production, mitogen-activated protein kinase activation, and Akt activation

Regulator of G-protein signaling 3 (RGS3) enhances the intrinsic rate at which G alpha (i) and G alpha (q) hydrolyze GTP to GDP, thereby limiting the duration in which GTP-G alpha (i) and GTP-G alpha (q) can activate effecters. Since GDP-G alpha subunits rapidly combine with free G beta gamma subunits to reform inactive heterotrimeric G-proteins, RGS3 and other RGS proteins may also reduce the amount of G beta gamma subunits available for effector interactions. Although RGS6, RGS7, and RGS11 bind GP, in the absence of a Gy subunit, RGS proteins are not known to directly influence G beta gamma signaling. Here we show that RGS3 binds G beta (1)gamma (2) subunits and limits their ability to trigger the production of inositol phosphates and the activation of Akt and mitogen-activated protein kinase. Go-expression of RGS3 with G beta (1)beta (2) inhibits G beta (1)gamma (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 G beta (1)gamma (2) 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 G beta (1)gamma (2) signaling in these assays. Consistent with the in vivo results, RGS3 inhibits G beta gamma -mediated activation of phospholipase C beta in vitro. Thus, RGS3 may limit G beta gamma signaling not only by virtue of its GTPase-activating protein activity for G alpha subunits, but also by directly interfering with the activation of effecters.