Functional interaction of G protein-coupled receptors of the adrenomedullin peptide family with accessory receptor-activity-modifying proteins (RAMP)

2002 ◽  
Vol 57 (1) ◽  
pp. 14-22 ◽  
Author(s):  
Walter Born ◽  
Roman Muff ◽  
Jan A. Fischer
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
Receptor Activity ◽  
Functional Interaction ◽  
Peptide Family ◽  
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.

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.

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 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

G-protein-coupled receptor allosterism: the promise and the problem(s)

2004 ◽  
Vol 32 (5) ◽  
pp. 873-877 ◽  
Author(s):  
A. Christopoulos ◽  
L.T. May ◽  
V.A. Avlani ◽  
P.M. Sexton
Keyword(s):  
G Protein ◽  
Binding Sites ◽  
G Protein Coupled Receptors ◽  
Receptor Activity ◽  
Screening Methods ◽  
Receptor Subtype ◽  
Allosteric Modulators ◽  
Physiological Regulation ◽  
Subtype Selectivity ◽  
G Protein Coupled

Allosteric modulators of G-protein-coupled receptors interact with binding sites that are topographically distinct from the orthosteric site recognized by the receptor's endogenous agonist. Allosteric ligands offer a number of advantages over orthosteric drugs, including the potential for greater receptor subtype selectivity and a more ‘physiological’ regulation of receptor activity. However, the manifestations of allosterism at G-protein-coupled receptors are quite varied, and significant challenges remain for the optimization of screening methods to ensure the routine detection and validation of allosteric ligands.

scholarly journals Molecular and functional interaction between GPR18 and cannabinoid CB2 G-protein-coupled receptors. Relevance in neurodegenerative diseases

2018 ◽  
Vol 157 ◽  
pp. 169-179 ◽  
Author(s):  
Irene Reyes-Resina ◽  
Gemma Navarro ◽  
David Aguinaga ◽  
Enric I. Canela ◽  
Clara T. Schoeder ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
G Protein ◽  
G Protein Coupled Receptors ◽  
Functional Interaction ◽  
G Protein Coupled

Adrenomedullin: receptor and signal transduction

2002 ◽  
Vol 30 (4) ◽  
pp. 432-437 ◽  
Author(s):  
D. M. Smith ◽  
H. A. Coppock ◽  
D. J. Withers ◽  
A. A. Owji ◽  
D. L. Hay ◽  
...  
Keyword(s):  
G Protein ◽  
Vascular Tissue ◽  
G Protein Coupled Receptors ◽  
Type Ii ◽  
Calcitonin Gene ◽  
Adrenomedullin Receptor ◽  
Receptor Activity Modifying Proteins ◽  
G Protein Coupled ◽  
Chemical Cross Linking

Adrenomedullin is a vascular tissue peptide and a member of the calcitonin family of peptides, which includes calcitonin, calcitonin-gene-related peptide (CGRP) and amylin. Its many biological actions are mediated via CGRP type 1 (CGRP1) receptors and by specific adrenomedullin receptors. Although the pharmacology of these receptors is distinct, they are both represented in molecular terms by the type II family G-protein-coupled receptor, calcitonin-receptor-like receptor (CRLR). The specificity here is defined by co-expression of receptor-activity-modifying proteins (RAMPs). CGRP1 receptors are represented by CRLR and RAMP1, and specific adrenomedullin receptors by CRLR and RAMP2 or 3. Here we discuss how CRLR/RAMP2 relates to adrenomedullin binding, pharmacology and pathophysiology, and how chemical cross-linking of receptor-ligand complexes in tissue relates to that in CRLR/RAMP2-expressing cells. CRLR, like other type II family G-protein-coupled receptors, signals via Gs and adenylate cyclase activation. We demonstrated that adrenomedullin signalling in cell lines expressing specific adrenomedullin receptors followed this expected pattern.

scholarly journals A short amino acid sequence containing tyrosine in the N-terminal region of G protein-coupled receptors is critical for their potential use as co-receptors for human and simian immunodeficiency viruses

2008 ◽  
Vol 89 (12) ◽  
pp. 3126-3136 ◽  
Author(s):  
Nobuaki Shimizu ◽  
Atsushi Tanaka ◽  
Atsushi Oue ◽  
Takahisa Mori ◽  
Chatchawann Apichartpiyakul ◽  
...  
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
Terminal Region ◽  
Receptor Activity ◽  
Formyl Peptide Receptor ◽  
Immunodeficiency Virus ◽  
Formyl Peptide ◽  
Short Amino Acid Sequence ◽  
G Protein Coupled ◽  
Hiv 1

Various G protein-coupled receptors (GPCRs) have the potential to work as co-receptors for human and simian immunodeficiency virus (HIV/SIV). HIV/SIV co-receptors have several tyrosines in their extracellular N-terminal region (NTR) as a common feature. However, the domain structure of the NTR that is critical for GPCRs to have co-receptor activity has not been identified. Comparative studies of different HIV/SIV co-receptors are an effective way to clarify the domain. These studies have been carried out only for the major co-receptors, CCR5 and CXCR4. A chemokine receptor, D6, has been shown to mediate infection of astrocytes with HIV-1. Recently, it was also found that an orphan GPCR, GPR1, and a formyl peptide receptor, FPRL1, work as potent HIV/SIV co-receptors in addition to CCR5 and CXCR4. To elucidate more about the domain of the NTR critical for HIV/SIV co-receptor activity, this study analysed the effects of mutations in the NTR on the co-receptor activity of D6, FPRL1 and GPR1 in addition to CCR5. The results identified a number of tyrosines that are indispensable for the activity of these co-receptors. The number and positions of those tyrosines varied among co-receptors and among HIV-1 strains. Moreover, it was found that a small domain of a few amino acids containing a tyrosine is critical for the co-receptor activity of GPR1. These findings will be useful in elucidating the mechanism that allows GPCRs to have the potential to act as HIV/SIV co-receptors.

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 ◽  
Author(s):  
Kerstin LEUTHÄUSER ◽  
Remo GUJER ◽  
Amaya ALDECOA ◽  
R. Anne MCKINNEY ◽  
Roman MUFF ◽  
...  
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
Receptor Activity ◽  
Ligand Recognition ◽  
G Protein Coupled
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