Review
Signaling at zero G: G-protein-independent functions for 7-TM receptors

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Abstract

Eukaryotic cells, whether free-living, single-celled microbes or components of complex metazoa, can sense environmental cues through specialized seven-transmembrane (7-TM) receptors (also called heptahelical or G-protein-coupled receptors). 7-TM receptors detect ‘inputs’ such as light, peptide hormones, neurotransmitters, pheromones, odorants, morphogens and chemoattractants, linking extracellular stimuli to intracellular signaling networks via heterotrimeric G proteins. Recently, this obligatory paradigm has been challenged. A growing body of evidence indicates that 7-TM receptors can also transmit extracellular signals through mechanisms that function independently of G-protein coupling. This review discusses pathways and protein interactions for 7-TM receptors signaling ‘at zero G’ in Dictyostelium and mammalian cells.

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.

References (56)

  • L Kim

    The novel tyrosine kinase ZAK1 activates GSK3 to direct cell fate specification

    Cell

    (1999)
  • L Kim et al.

    GSK3, a master switch regulating cell fate specification and tumorigenesis

    Curr. Opin. Genet. Dev.

    (2000)
  • O.B Goodman

    Arrestin/clathrin interaction. Localization of the arrestin binding locus to the clathrin terminal domain

    J. Biol. Chem.

    (1997)
  • J.G Krupnick

    Modulation of the arrestin–clathrin interaction in cells. Characterization of β-arrestin dominant-negative mutants

    J. Biol. Chem.

    (1997)
  • S.A Laporte

    The interaction of β-arrestin with the AP-2 adaptor is required for the clustering of beta 2-adrenergic receptor into clathrin-coated pits

    J. Biol. Chem.

    (2000)
  • Y Ma

    Src tyrosine kinase is a novel direct effector of G proteins

    Cell

    (2000)
  • W.E Miller

    β-arrestin1 interacts with the catalytic domain of the tyrosine kinase c-SRC. Role of β-arrestin1-dependent targeting of c-SRC in receptor endocytosis

    J. Biol. Chem.

    (2000)
  • G.J Bhat

    Activation of the STAT pathway by angiotensin II in T3CHO/AT1A cells. Cross-talk between angiotensin II and interleukin-6 nuclear signaling

    J. Biol. Chem.

    (1995)
  • I Guillet-Deniau

    Identification and localization of a skeletal muscle secrotonin 5-HT2A receptor coupled to the Jak/STAT pathway

    J. Biol. Chem.

    (1997)
  • M.S Ali

    Dependence on the motif YIPP for the physical association of Jak2 kinase with the intracellular carboxyl tail of the angiotensin II AT1 receptor

    J. Biol. Chem.

    (1997)
  • M.S Ali

    Jak2 acts as both a STAT1 kinase and as a molecular bridge linking STAT1 to the angiotensin II AT1 receptor

    J. Biol. Chem.

    (2000)
  • J Sun

    Isolation of PSD-Zip45, a novel Homer/vesl family protein containing leucine zipper motifs, from rat brain

    FEBS Lett.

    (1998)
  • B Xiao

    Homer regulates the association of group 1 metabotropic glutamate receptors with multivalent complexes of homer-related, synaptic proteins

    Neuron

    (1998)
  • J.C Tu

    Homer binds a novel proline-rich motif and links group 1 metabotropic glutamate receptors with IP3 receptors

    Neuron

    (1998)
  • J.C Tu

    Coupling of mGluR/Homer and PSD-95 complexes by the Shank family of postsynaptic density proteins

    Neuron

    (1999)
  • S Naisbitt

    Shank, a novel family of postsynaptic density proteins that binds to the NMDA receptor/PSD-95/GKAP complex and cortactin

    Neuron

    (1999)
  • R.A Hall

    G protein-coupled receptor kinase 6A phosphorylates the Na(+)/H(+) exchanger regulatory factor via a PDZ domain-mediated interaction

    J. Biol. Chem.

    (1999)
  • T Liu

    Activation of rat frizzled-1 promotes Wnt signaling and differentiation of mouse F9 teratocarcinoma cells via pathways that require Galpha(q) and Galpha(o) function

    J.Biol. Chem.

    (1999)
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