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Novel receptor partners and function of receptor activity-modifying proteins
Arthur Christopoulos1, George Christopoulos, Maria Morfis
1Department of Pharmacology and the Howard Florey Institute, The University of Melbourne, Victoria 3010, Australia.
The Journal of Biological Chemistry
|November 26, 2002
Summary
Receptor Activity-Modifying Proteins (RAMPs) interact with more G protein-coupled receptors (GPCRs) than previously known. This interaction can alter cellular signaling pathways, suggesting broader roles for RAMPs in cell function.
Area of Science:
- Biochemistry
- Cell Biology
- Molecular Pharmacology
Background:
- Receptor Activity-Modifying Proteins (RAMPs) are accessory proteins known to heterodimerize with the calcitonin receptor-like receptor (CL receptor) and calcitonin receptor (CTR).
- RAMPs have a wider distribution than CTR and CL receptor, implying additional functions beyond known receptor heterodimerization.
- The precise range of receptors interacting with RAMPs and the functional consequences of these interactions remain incompletely understood.
Purpose of the Study:
- To investigate the potential for RAMP interaction with Class II G protein-coupled receptors (GPCRs) beyond the CL receptor and CTR.
- To identify specific RAMPs that interact with additional GPCRs.
- To determine the functional impact of RAMP-GPCR interactions on cellular signaling.
Main Methods:
- Immunofluorescence confocal microscopy was employed to visualize RAMP-receptor interactions.
- Radioligand binding assays in COS-7 cells were used to assess phenotypic changes in receptor activity.
- Agonist-mediated phosphoinositide hydrolysis and cAMP stimulation assays were performed to evaluate signaling modulation.
Main Results:
- RAMPs were shown to interact with at least four additional GPCRs: VPAC1 receptor (VPAC1R) with all three RAMPs, glucagon and PTH1 receptors with RAMP2, and PTH2 receptor with RAMP3.
- VPAC1R-RAMP complexes did not exhibit altered phenotypic behavior compared to VPAC1R alone.
- The VPAC1R-RAMP2 heterodimer demonstrated enhanced agonist-mediated phosphoinositide hydrolysis without affecting cAMP stimulation.
Conclusions:
- RAMPs interact with a broader spectrum of GPCRs than previously recognized.
- RAMP-GPCR interactions can lead to functional consequences, such as modulation of specific signaling pathways like phosphoinositide hydrolysis.
- These findings suggest a more general role for RAMPs in regulating cellular signaling through diverse GPCRs.