Editors' ChoiceG Proteins

The "Other" G Protein Corrals PKA

Science's STKE  19 Dec 2006:
Vol. 2006, Issue 366, pp. tw425
DOI: 10.1126/stke.3662006tw425

Whereas Gs- and Gi-type heterotrimeric GTP-binding proteins (G proteins) are well known for the stimulatory and inhibitory effects of their α-subunits on adenylyl cyclase, the known effects of Go--the most abundant brain G protein--are mostly mediated by the Gβγ dimer, with specific functions of Gαo remaining unclear. Noting that evidence exists both for direct effects of Gαo and for crosstalk between Go and cAMP-dependent protein kinase (PKA) signaling, Ghil et al. looked for possible interactions between Go and PKA. Both in vitro analysis and immunoprecipitation of 293T cells overexpressing Gαo and PKA regulatory and catalytic subunits (RIIβ and Cα) indicated that Gαo bound PKA catalytic subunits. Gαi did not bind Cα, and analysis of Gαi-Gαo chimeras indicated that Gαo bound PKA through its GTPase domain. Gαo did not inhibit the catalytic activity of purified Cα; however, immunocytochemical analysis of COS7 cells transfected with FLAG-tagged Gα constructs and stimulated with forskolin indicated that the Gαo-Cα interaction inhibited translocation of Cα to the nucleus. Moreover, pharmacological analysis of GH4C1 rat pituitary tumor cells (containing endogenous Go and PKA) indicated that Go inhibited not only Cα translocation to the nucleus but also PKA-dependent cAMP response element-binding protein (CREB) phosphorylation. In contrast, Gαο spared--or even facilitated--the cytosolic effects of PKA. Thus, the authors propose that, by binding Cα, Gαo 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 Go. Proc. Natl. Acad. Sci. U.S.A. 103, 19158-19163 (2006). [Abstract] [Full Text]