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J. Biol. Chem. 278 (5): 3293-3297

© 2003 by The American Society for Biochemistry and Molecular Biology, Inc.

Novel Receptor Partners and Function of Receptor Activity-modifying Proteins*

Arthur ChristopoulosDagger §, George Christopoulos§, Maria Morfis§, Madhara Udawela§, Marc Laburthe||, Alain Couvineau||, Kenji Kuwasako**, Nanda Tilakaratne§, and Patrick M. Sexton§Dagger Dagger

From the Dagger  Department of Pharmacology and the § Howard Florey Institute, The University of Melbourne, Victoria 3010, Australia, the || Department of Neuroendocrinology and Cell Biology, INSERM U410, Faculté de Médecine Xavier Bichat, 75018, Paris, France, and the ** First Department of Internal Medicine, Miyazaki Medical College, Miyazaki 889-1692, Japan

The receptor activity-modifying proteins (RAMPs) comprise a family of three accessory proteins that heterodimerize with the calcitonin receptor-like receptor (CL receptor) or with the calcitonin receptor (CTR) to generate different receptor phenotypes. However, RAMPs are more widely distributed across cell and tissue types than the CTR and CL receptor, suggesting additional roles for RAMPs in cellular processes. We have investigated the potential for RAMP interaction with a number of Class II G protein-coupled receptors (GPCRs) in addition to the CL receptor and the CTR. Using immunofluorescence confocal microscopy, we demonstrate, for the first time, that RAMPs interact with at least four additional receptors, the VPAC1 vasoactive intestinal polypeptide/pituitary adenylate cyclase-activating peptide receptor with all three RAMPs; the glucagon and PTH1 parathyroid hormone receptors with RAMP2; and the PTH2 receptor with RAMP3. Unlike the interaction of RAMPs with the CL receptor or the CTR, VPAC1R-RAMP complexes do not show altered phenotypic behavior compared with the VPAC1R alone, as determined using radioligand binding in COS-7 cells. However, the VPAC1R-RAMP2 heterodimer displays a significant enhancement of agonist-mediated phosphoinositide hydrolysis with no change in cAMP stimulation compared with the VPAC1R alone. Our findings identify a new functional consequence of RAMP-receptor interaction, suggesting that RAMPs play a more general role in modulating cell signaling through other GPCRs than is currently appreciated.

* This work was funded by National Health and Medical Research Council (NHMRC) Grants 990024 and 145702.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

A C. R. Roper senior research fellow of the Faculty of Medicine, Dentistry, and Health Sciences, University of Melbourne.

Dagger Dagger A senior research fellow of the National Health and Medical Research Council of Australia. To whom correspondence should be addressed. Tel.: 61-3-8344-7334; Fax: 61-3-9348-1707; E-mail: p.sexton@hfi.unimelb.edu.au.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.

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