G Proteins The "Other" G Protein Corrals PKA

Elizabeth M. Adler

Science’s STKE, AAAS, Washington, DC 20005, USA

Whereas G_s- and G_i-type heterotrimeric GTP-binding proteins (G proteins) are well known for the stimulatory and inhibitory effects of their -subunits on adenylyl cyclase, the known effects of G_o--the most abundant brain G protein--are mostly mediated by the G dimer, with specific functions of G_o remaining unclear. Noting that evidence exists both for direct effects of G_o and for crosstalk between G_o and cAMP-dependent protein kinase (PKA) signaling, Ghil et al. looked for possible interactions between G_o and PKA. Both in vitro analysis and immunoprecipitation of 293T cells overexpressing G_o and PKA regulatory and catalytic subunits (RII and C) indicated that G_o bound PKA catalytic subunits. G_i did not bind C, and analysis of G_i-G_o chimeras indicated that G_o bound PKA through its GTPase domain. G_o did not inhibit the catalytic activity of purified C; however, immunocytochemical analysis of COS7 cells transfected with FLAG-tagged G constructs and stimulated with forskolin indicated that the G_o-C interaction inhibited translocation of C to the nucleus. Moreover, pharmacological analysis of GH4C1 rat pituitary tumor cells (containing endogenous G_o and PKA) indicated that G_o inhibited not only C translocation to the nucleus but also PKA-dependent cAMP response element-binding protein (CREB) phosphorylation. In contrast, G_o spared--or even facilitated--the cytosolic effects of PKA. Thus, the authors propose that, by binding C, G_o directs its subcellular localization and thereby regulates its downstream effects.

S. Ghil, J.-M. Choi, S.-S. Kim, Y.-D. Lee, Y. Liao, L. Birnbaumer, H. Suh-Kim, Compartmentalization of protein kinase A signaling by the heterotrimeric G protein G_o. Proc. Natl. Acad. Sci. U.S.A. 103, 19158-19163 (2006). [Abstract] [Full Text]