Abstract
G protein coupled receptors (GPCRs) are major targets for therapeutic drugs, hence understanding the mechanism of signal transduction through these receptors is crucial for the development of novel therapies. Regulators of G protein signaling (RGS) proteins accelerate the deactivation of G proteins by acting as GTPase activating proteins (GAPs) towards Gα subunits. The R7 subfamily of RGS proteins contains a Dishevelled, Egl‐10, Pleckstrin (DEP) and Gγ like (GGL) domain along with the characteristic RGS domain. It is via the GGL domain that R7 RGS proteins form a stable complex with the Gβ subunit, Gβ5 in vivo. Recently, an additional member of this complex R7 binding protein (R7BP) has been identified. R7BP binds to all R7 RGS proteins via the DEP domain. This interaction facilitates the recruitment of the RGS7‐Gβ5 complex to the plasma membrane. Previously we demonstrated that RGS7‐Gβ5 attenuates Ca2+ mobilization from M3 receptor in transfected cells. In this study, using Fura 2, we show that RGS7‐Gβ5 acts in a receptor‐specific manner, as it does not have an effect on M1, another Gq‐coupled GPCR. We also investigated the effect of R7BP on the activity of RGS7‐Gβ5 and found that it diminishes the negative regulation of M3 receptor signaling. Additional insights into this molecular mechanism were obtained via microscopy and GST pulldown assays.
This research is supported by NIH grant GM 060019 (V.Z.S.).