Receptor activity modifying proteins (RAMPs) interact with the VPAC 2 receptor and CRF1 receptors and modulate their function

Denise Laura Wootten, Helena Lindmark, Mahita Kadmiel, Helen H Willcockson, Kathleen M Caron, James Barwell, Tomas Drmota, David R Poyner

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Abstract

Background and Purpose Although it is established that the receptor activity modifying proteins (RAMPs) can interact with a number of GPCRs, little is known about the consequences of these interactions. Here the interaction of RAMPs with the glucagon-like peptide 1 receptor (GLP-1 receptor), the human vasoactive intestinal polypeptide/pituitary AC-Activating peptide 2 receptor (VPAC2) and the type 1 corticotrophin releasing factor receptor (CRF1) has been examined. Experimental Approach GPCRs were co-transfected with RAMPs in HEK 293S and CHO-K1 cells. Cell surface expression of RAMPs and GPCRs was examined by elisa. Where there was evidence for interactions, agonist-stimulated cAMP production, Ca2+ mobilization and GTP?S binding to Gs, Gi, G12 and Gq were examined. The ability of CRF to stimulate adrenal corticotrophic hormone release in Ramp2+/- mice was assessed. Key Results The GLP-1 receptor failed to enhance the cell surface expression of any RAMP. VPAC2 enhanced the cell surface expression of all three RAMPs. CRF1 enhanced the cell surface expression of RAMP2; the cell surface expression of CRF1 was also increased. There was no effect on agonist-stimulated cAMP production. However, there was enhanced G-protein coupling in a receptor and agonist-dependent manner. The CRF1: RAMP2 complex resulted in enhanced elevation of intracellular calcium to CRF and urocortin 1 but not sauvagine. In Ramp2+/- mice, there was a loss of responsiveness to CRF. Conclusions and Implications The VPAC2 and CRF1 receptors interact with RAMPs. This modulates G-protein coupling in an agonist-specific manner. For CRF1, coupling to RAMP2 may be of physiological significance.
Original languageEnglish
Pages (from-to)822 - 834
Number of pages13
JournalBritish Journal of Pharmacology
Volume168
Issue number4
DOIs
Publication statusPublished - 2013
Externally publishedYes

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