Trends in Biochemical Sciences
ReviewSignaling at zero G: G-protein-independent functions for 7-TM receptors
Section snippets
G-protein-coupled receptor signaling in Dictyostelium
Dictyostelium employs an elegant survival mechanism when faced with a depleted food supply. Single ameboid cells feed on bacteria and proliferate. Upon starvation, a developmental program ensues in which free-living cells migrate in response to an oscillating, extracellular release of the chemoattractant cAMP. Approximately 10 5 cells aggregate into a mound-like structure, and morphogenesis and cytodifferentiation then lead to a terminal structure in which spore cells are supported by a stem of
Ca2+ influx
cAMP-stimulated Ca2+ entry into Dictyostelium is a CAR-dependent and rapid event, initiating 5–10 seconds post-stimulation 7, 8. CAR1 mediates Ca2+ influx during early aggregation and mutations in the third intracellular loop of CAR1 impair this process 2. Ca2+ uptake is observed in cell lines that specifically express only CAR1, CAR2, CAR3 or CAR4; these cells respond with a maximal influx of Ca2+ in a dose-dependent manner to cAMP that is dependent on individual receptor affinity for the
7-TM receptor–non-G-protein interactions in mammalian cells
Activated GPCRs are substrates for GRKs, and phosphorylated GPCRs are binding targets for the non-G-protein arrestins. Although it has been apparent for many years that 7-TM receptors had the capacity to interact with these non-G proteins, only recently has the impact of these interactions with respect to additional signaling pathways been appreciated.
Lose the G-
The family of cell-surface receptors that require coupling to G-protein transducers for functional signaling is vast and diverse. The isolation of cDNAs for G-protein-coupled rhodopsin and β-adrenoceptors enabled a comparison that indicated a shared structural configuration characterized by 7-TM or heptahelical domains. With creative insight, it was further suggested that this structural organization might be a distinctive and common characteristic of all GPCR family members 55.
The cAMP
Note added in proof
Recent studies by Luttrell et al. 56 have extended the regulatory pathways for β-arrestin-mediated signaling through the ERKs; in complex with angiotensin II type1a receptors, β-arrestin functions as a scaffold to promote Raf- and Mek-mediated activation of ERK2.
Acknowledgements
We would like to thank Carole Parent, William Simonds and Dean Londos for critically reading this manuscript. We also thank Lisa Kreppel, Leung Kim, Pamela Schwartzberg and Erika Shugart for continued engaging discussions on topics herein.
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