Volume 11 Supplement 2

17th Scientific Symposium of the Austrian Pharmacological Society (APHAR)

Open Access

The D-type prostanoid (DP) receptor enhances the signaling of chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2)

  • Miriam Sedej1,
  • Ralf Schröder2,
  • Kathrin Bell2,
  • Wolfgang Platzer1,
  • Evi Kostenis2,
  • Ákos Heinemann1 and
  • Maria Waldhoer1, 3Email author
BMC Pharmacology201111(Suppl 2):A58

https://doi.org/10.1186/1471-2210-11-S2-A58

Published: 5 September 2011

Background

Prostaglandin (PG) D2 is substantially involved in allergic responses and signals via the seven-transmembrane-spanning/G protein-coupled receptors, chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) and D-type prostanoid (DP) receptor. While the proinflammatory function of CRTH2 is well recognized and CRTH2 is hence considered as an important emerging pharmacotherapeutic target, the role of the DP receptor in mediating the biological effects of PGD2 in allergic inflammation has remained unclear.

Methods

The cross-talk of CRTH2 and DP receptors was investigated using both a recombinant HEK293 cell model and human eosinophils in Ca2+ mobilization assays, co-immunoprecipitation and radioligand binding assays.

Results

We show that CRTH2 and DP receptors modulate each other’s signalling properties and form CRTH2/DP heteromers without altering their ligand-binding capacities. We find that the DP receptor amplifies the CRTH2-induced Ca2+ release from intracellular stores and, coincidentally, forfeits its own signalling potency. Moreover, desensitization or pharmacological blockade of the DP receptor hinders CRTH2-mediated signal transduction. Pharmacological blockade of Gαq/11 proteins abolishes the Ca2+ response to both CRTH2 and DP agonists, while inhibition of Gαi proteins selectively attenuates the CRTH2-mediated response but not the DP signal.

Conclusions

Our data demonstrate the capacity of DP receptors to amplify the biological response to CRTH2 activation. Therefore, the CRTH2/DP heteromer may not only represent a functional signalling unit for PGD2 but also a potential target for development of heteromer-directed therapies to treat allergic diseases.

Authors’ Affiliations

(1)
Institute of Experimental and Clinical Pharmacology, Medical University of Graz
(2)
Institute of Pharmaceutical Biology, University of Bonn
(3)
Hagedorn Research Institute, Novo Nordisk A/S

Copyright

© Sedej et al; licensee BioMed Central Ltd. 2011

This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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