The functional relevance of G protein receptor associated proteins exemplified by the receptor-activity-modifying proteins (RAMP)

2002 ◽  
Vol 30 (3) ◽  
pp. A60-A60
Author(s):  
J. A. Fischer
Keyword(s):  
G Protein ◽  
Receptor Activity ◽  
Protein Receptor ◽  
Associated Proteins ◽  
Functional Relevance ◽  
Receptor Activity Modifying Proteins

Functional relevance of G-protein-coupled-receptor-associated proteins, exemplified by receptor-activity-modifying proteins (RAMPs)

2002 ◽  
Vol 30 (4) ◽  
pp. 455-460 ◽  
Author(s):  
J. A. Fischer ◽  
R. Muff ◽  
W. Born
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
Receptor Activity ◽  
Orphan Receptor ◽  
Cgrp Receptor ◽  
Associated Proteins ◽  
Functional Relevance ◽  
Receptor Activity Modifying Proteins ◽  
Close Relatives ◽  
G Protein Coupled

The calcitonin (CT) receptor (CTR) and the CTR-like receptor (CRLR) are close relatives within the type II family of G-protein-coupled receptors, demonstrating sequence identity of 50%. Unlike the interaction between CT and CTR, receptors for the related hormones and neuropeptides amylin, CT-gene-related peptide (CGRP) and adrenomedullin (AM) require one of three accessory receptor-activity-modifying proteins (RAMPs) for ligand recognition. An amylin/CGRP receptor is revealed when CTR is co-expressed with RAMP1. When complexed with RAMP3, CTR interacts with amylin alone. CRLR, initially classed as an orphan receptor, is a CGRP receptor when co-expressed with RAMP1. The same receptor is specific for AM in the presence of RAMP2. Together with human RAMP3, CRLR defines an AM receptor, and with mouse RAMP3 it is a low-affinity CGRP/AM receptor. CTR-RAMP1, antagonized preferentially by salmon CT-(8–32) and not by CGRP-(8–37), and CRLR-RAMP1, antagonized by CGRP-(8–37), are two CGRP receptor isotypes. Thus amylin and CGRP interact specifically with heterodimeric complexes between CTR and RAMP1 or RAMP3, and CGRP and AM interact with complexes between CRLR and RAMP1, RAMP2 or RAMP3.

Receptor Activity Modifying Proteins Have Limited Effects on the Class B G Protein-Coupled Receptor Calcitonin Receptor-Like Receptor Stalk

Biochemistry ◽  
2018 ◽  
Vol 57 (8) ◽  
pp. 1410-1422 ◽  
Author(s):  
Michael L. Garelja ◽  
Christina A. Walker ◽  
Andrew Siow ◽  
Sung H. Yang ◽  
Paul W.R. Harris ◽  
...  
Keyword(s):  
G Protein ◽  
Receptor Activity ◽  
Calcitonin Receptor ◽  
G Protein Coupled Receptor ◽  
Class B ◽  
Receptor Activity Modifying Proteins ◽  
G Protein Coupled

scholarly journals An allosteric role for receptor activity-modifying proteins in defining GPCR pharmacology

2016 ◽  
Vol 2 (1) ◽  
Author(s):  
Joseph J Gingell ◽  
John Simms ◽  
James Barwell ◽  
David R Poyner ◽  
Harriet A Watkins ◽  
...  
Keyword(s):  
G Protein ◽  
Protein Interaction ◽  
G Protein Coupled Receptors ◽  
Receptor Activity ◽  
Calcitonin Receptor ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Receptor Activity Modifying Proteins ◽  
G Protein Coupled ◽  
Insight Into

Abstract G protein-coupled receptors are allosteric proteins that control transmission of external signals to regulate cellular response. Although agonist binding promotes canonical G protein signalling transmitted through conformational changes, G protein-coupled receptors also interact with other proteins. These include other G protein-coupled receptors, other receptors and channels, regulatory proteins and receptor-modifying proteins, notably receptor activity-modifying proteins (RAMPs). RAMPs have at least 11 G protein-coupled receptor partners, including many class B G protein-coupled receptors. Prototypic is the calcitonin receptor, with altered ligand specificity when co-expressed with RAMPs. To gain molecular insight into the consequences of this protein–protein interaction, we combined molecular modelling with mutagenesis of the calcitonin receptor extracellular domain, assessed in ligand binding and functional assays. Although some calcitonin receptor residues are universally important for peptide interactions (calcitonin, amylin and calcitonin gene-related peptide) in calcitonin receptor alone or with receptor activity-modifying protein, others have RAMP-dependent effects, whereby mutations decreased amylin/calcitonin gene-related peptide potency substantially only when RAMP was present. Remarkably, the key residues were completely conserved between calcitonin receptor and AMY receptors, and between subtypes of AMY receptor that have different ligand preferences. Mutations at the interface between calcitonin receptor and RAMP affected ligand pharmacology in a RAMP-dependent manner, suggesting that RAMP may allosterically influence the calcitonin receptor conformation. Supporting this, molecular dynamics simulations suggested that the calcitonin receptor extracellular N-terminal domain is more flexible in the presence of receptor activity-modifying protein 1. Thus, RAMPs may act in an allosteric manner to generate a spectrum of unique calcitonin receptor conformational states, explaining the pharmacological preferences of calcitonin receptor-RAMP complexes. This provides novel insight into our understanding of G protein-coupled receptor-protein interaction that is likely broadly applicable for this receptor class.

scholarly journals Receptor-activity-modifying protein 1 forms heterodimers with two G-protein-coupled receptors to define ligand recognition

2000 ◽  
Vol 351 (2) ◽  
pp. 347-351 ◽  
Author(s):  
Kerstin LEUTHÄUSER ◽  
Remo GUJER ◽  
Amaya ALDECOA ◽  
R. ANNE McKINNEY ◽  
Roman MUFF ◽  
...  
Keyword(s):  
Confocal Microscopy ◽  
G Protein ◽  
G Protein Coupled Receptors ◽  
Receptor Activity ◽  
Cross Linking ◽  
Human Calcitonin ◽  
Camp Production ◽  
Surface Complexes ◽  
Receptor Activity Modifying Proteins ◽  
G Protein Coupled

Receptor-activity-modifying proteins (RAMPs) with single transmembrane domains define the function of two G-protein-coupled receptors of the B family. Cell-surface complexes of human RAMP1 (hRAMP1) and human calcitonin (CT) receptor isotype 2 (hCTR2) or rat CT-receptor-like receptor (rCRLR) have now been identified through protein cross-linking, co-immunoprecipitation and confocal microscopy. They are two distinct CT-gene-related peptide (CGRP) receptors coupled to cAMP production and pharmacologically distinguished by the CT and CGRP antagonists salmon CT(8-32) and human or rat CGRP(8-37). Thus direct molecular interactions of hRAMP1 with hCTR2 or rCRLR are required for CGRP recognition. hCTR2, moreover, adopts non-traditional functions through its association with hRAMP1.

Receptor activity-modifying proteins; multifunctional G protein-coupled receptor accessory proteins

2016 ◽  
Vol 44 (2) ◽  
pp. 568-573 ◽  
Author(s):  
Debbie L. Hay ◽  
Christopher S. Walker ◽  
Joseph J. Gingell ◽  
Graham Ladds ◽  
Christopher A. Reynolds ◽  
...  
Keyword(s):  
Ligand Binding ◽  
G Protein ◽  
Drug Targeting ◽  
Receptor Expression ◽  
Receptor Activity ◽  
Calcitonin Receptor ◽  
G Protein Coupled Receptor ◽  
Recent Developments ◽  
Receptor Activity Modifying Proteins ◽  
G Protein Coupled

Receptor activity-modifying proteins (RAMPs) are single pass membrane proteins initially identified by their ability to determine the pharmacology of the calcitonin receptor-like receptor (CLR), a family B G protein-coupled receptor (GPCR). It is now known that RAMPs can interact with a much wider range of GPCRs. This review considers recent developments on the structure of the complexes formed between the extracellular domains (ECDs) of CLR and RAMP1 or RAMP2 as these provide insights as to how the RAMPs direct ligand binding. The range of RAMP interactions is also considered; RAMPs can interact with numerous family B GPCRs as well as examples of family A and family C GPCRs. They influence receptor expression at the cell surface, trafficking, ligand binding and G protein coupling. The GPCR–RAMP interface offers opportunities for drug targeting, illustrated by examples of drugs developed for migraine.

scholarly journals Receptor Activity-Modifying Proteins Differentially Modulate the G Protein-Coupling Efficiency of Amylin Receptors

Endocrinology ◽  
2008 ◽  
Vol 149 (11) ◽  
pp. 5423-5431 ◽  
Author(s):  
Maria Morfis ◽  
Nanda Tilakaratne ◽  
Sebastian G. B. Furness ◽  
George Christopoulos ◽  
Tim D. Werry ◽  
...  
Keyword(s):  
G Protein ◽  
Coupling Efficiency ◽  
Receptor Activity ◽  
G Protein Coupling ◽  
Hek 293 ◽  
Protein Coupling ◽  
Intracellular Ca ◽  
Fold Induction ◽  
Receptor Activity Modifying Proteins ◽  
Receptor Phenotype

Receptor activity-modifying proteins (RAMPs) 1, 2, and 3 are prototypic G protein-coupled receptor accessory proteins that can alter not only receptor trafficking but also receptor phenotype. Specific RAMP interaction with the calcitonin receptor (CTR) generates novel and distinct receptors for the peptide amylin; however, the role of RAMPs in receptor signaling is not understood. The current study demonstrates that RAMP interaction with the CTRa in COS-7 or HEK-293 cells leads to selective modulation of signaling pathways activated by the receptor complex. There was a 20- to 30-fold induction in amylin potency at CTR/RAMP1 (AMY1) and CTR/RAMP3 (AMY3) receptors, compared with CTR alone, for formation of the second-messenger cAMP that parallels an increase in amylin binding affinity. In contrast, only 2- to 5-fold induction of amylin potency was seen for mobilization of intracellular Ca++ or activation of ERK1/2. In addition, in COS-7 cells, the increase in amylin potency for Ca++ mobilization was 2-fold greater for AMY3 receptors, compared with AMY1 receptors and this paralleled the relative capacity of overexpression of Gαq proteins to augment induction of high affinity 125I-amylin binding. These data demonstrate that RAMP-complexed receptors have a different signaling profile to CTRs expressed in the absence of RAMPs, and this is likely due to direct effects of the RAMP on G protein-coupling efficiency.

Sign in / Sign up

Export Citation Format

Share Document