Receptor activity modifying proteins (RAMPs) interact with the VPAC2 receptor and CRF1 receptors and modulate their function

Br J Pharmacol. 2013 Feb;168(4):822-34. doi: 10.1111/j.1476-5381.2012.02202.x.


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 (VPAC(2)) and the type 1 corticotrophin releasing factor receptor (CRF(1)) 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, Ca(2+) mobilization and GTPγS binding to G(s), G(i), G(12) and G(q) 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. VPAC(2) enhanced the cell surface expression of all three RAMPs. CRF(1) enhanced the cell surface expression of RAMP2; the cell surface expression of CRF(1) 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 CRF(1) : 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 VPAC(2) and CRF(1) receptors interact with RAMPs. This modulates G-protein coupling in an agonist-specific manner. For CRF(1), coupling to RAMP2 may be of physiological significance.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adrenocorticotropic Hormone / blood
  • Animals
  • CHO Cells
  • Calcium / metabolism
  • Cricetinae
  • Cricetulus
  • Cyclic AMP / metabolism
  • Enzyme-Linked Immunosorbent Assay
  • Guanosine 5'-O-(3-Thiotriphosphate) / metabolism
  • HEK293 Cells
  • Humans
  • Mice
  • Mice, Knockout
  • Protein Binding
  • Real-Time Polymerase Chain Reaction
  • Receptor Activity-Modifying Protein 2 / genetics
  • Receptor Activity-Modifying Protein 2 / metabolism
  • Receptor Activity-Modifying Proteins / metabolism*
  • Receptors, Corticotropin-Releasing Hormone / metabolism*
  • Receptors, Vasoactive Intestinal Peptide, Type II / metabolism*
  • Transfection


  • Ramp2 protein, mouse
  • Receptor Activity-Modifying Protein 2
  • Receptor Activity-Modifying Proteins
  • Receptors, Corticotropin-Releasing Hormone
  • Receptors, Vasoactive Intestinal Peptide, Type II
  • Guanosine 5'-O-(3-Thiotriphosphate)
  • CRF receptor type 1
  • Adrenocorticotropic Hormone
  • Cyclic AMP
  • Calcium