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A new phospholipase-C–calcium signalling pathway mediated by cyclic AMP and a Rap GTPase

Nature Cell Biology volume 3, pages 1020–1024 (2001)Cite this article

Abstract

Stimulation of phosphoinositide-hydrolysing phospholipase C (PLC) generating inositol-1,4,5-trisphosphate is a major calcium signalling pathway used by a wide variety of membrane receptors, activating distinct PLC-β or PLC-γ isoforms1,2,3,4. Here we report a new PLC and calcium signalling pathway that is triggered by cyclic AMP (cAMP) and mediated by a small GTPase of the Rap family. Activation of the adenylyl cyclase-coupled β2-adrenoceptor expressed in HEK-293 cells or the endogenous receptor for prostaglandin E1 in N1E-115 neuroblastoma cells induced calcium mobilization and PLC stimulation, seemingly caused by cAMP formation, but was independent of protein kinase A (PKA). We provide evidence that these receptor responses are mediated by a Rap GTPase, specifically Rap2B, activated by a guanine-nucleotide-exchange factor (Epac) regulated by cAMP5,6, and involve the recently identified PLC-ɛ isoform7,8,9.

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Figure 1: β2-AR- and forskolin-induced calcium and PLC signalling.
Figure 2: β2-AR- and forskolin-induced PLC and calcium signalling is independent of PKA and potentiated by Epac1.
Figure 3: Inhibition of β2-AR- and forskolin-induced PLC and calcium signalling by toxin B-1470 and an inactive Rap2B mutant.
Figure 4: Potentiation of β2-AR- and forskolin-induced PLC and calcium signalling by PLC-ɛ.
Figure 5: Influence of Rap2B on PLC-ɛ activity.

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Acknowledgements

We thank K. Baden, M. Hagedorn, H. Geldermann, D. Petermeyer, M. Michel and A. Rueppel for expert technical assistance, and R. Jockers, J. de Gunzburg, J. L. Bos, A. Wittinghofer and C. von Eichel-Streiber for providing various DNA constructs and proteins. This work was supported by the Deutsche Forschungsgemeinschaft, the Interne Forschungsförderung Essen (IFORES), the Fonds der Chemischen Industrie and the Council of Earth and Life Sciences and Chemical Sciences of The Netherlands Organisation for Scientific Research.

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Author notes

  1. Martina Schmidt and Sandrine Evellin: These authors contributed equally to this work

Authors and Affiliations

  1. Institut für Pharmakologie, Universitätsklinikum Essen, Essen, 45122, Germany

    Martina Schmidt, Sandrine Evellin, Paschal A. Oude Weernink, Frank vom Dorp & Karl H. Jakobs

  2. Max-Planck-Institut für Molekulare Physiologie, Dortmund, 44227, Germany

    Holger Rehmann

  3. Department of Physiological Chemistry and Centre for Biomedical Genetics, UMC Utrecht, Utrecht, 3584 CG, The Netherlands

    Holger Rehmann

  4. Departments of Pathology and Pharmacology, Northwestern University Medical School, Chicago, 60611-3008, Illinois, USA

    Jon W. Lomasney

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  1. Martina Schmidt
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Correspondence to Martina Schmidt.

Supplementary information

Figure S1

PGE1- and forskolin-induced PLC stimulation in N1E-115 neuroblastoma cells: role of cAMP, PKA, Epac1, Rap2B and PLC-ɛ (PDF 44 kb)

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Schmidt, M., Evellin, S., Weernink, P. et al. A new phospholipase-C–calcium signalling pathway mediated by cyclic AMP and a Rap GTPase. Nat Cell Biol 3, 1020–1024 (2001). https://doi.org/10.1038/ncb1101-1020

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