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 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 Activating autoantibodies against G protein-coupled receptors in narcolepsy type 1

2021 ◽  
Vol 77 ◽  
pp. 82-87
Author(s):  
Maija Orjatsalo ◽  
Eemil Partinen ◽  
Gerd Wallukat ◽  
Anniina Alakuijala ◽  
Markku Partinen
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
Activating Autoantibodies ◽  
G Protein Coupled

scholarly journals Similarity between class A and class B G-protein-coupled receptors exemplified through calcitonin gene-related peptide receptor modelling and mutagenesis studies

2013 ◽  
Vol 10 (79) ◽  
pp. 20120846 ◽  
Author(s):  
Shabana Vohra ◽  
Bruck Taddese ◽  
Alex C. Conner ◽  
David R. Poyner ◽  
Debbie L. Hay ◽  
...  
Keyword(s):  
G Protein ◽  
Calcitonin Gene Related Peptide ◽  
G Protein Coupled Receptors ◽  
Cgrp Receptor ◽  
Conserved Residues ◽  
Related Peptide ◽  
Class A ◽  
Calcitonin Gene ◽  
Class B ◽  
G Protein Coupled

Modelling class B G-protein-coupled receptors (GPCRs) using class A GPCR structural templates is difficult due to lack of homology. The plant GPCR, GCR1, has homology to both class A and class B GPCRs. We have used this to generate a class A–class B alignment, and by incorporating maximum lagged correlation of entropy and hydrophobicity into a consensus score, we have been able to align receptor transmembrane regions. We have applied this analysis to generate active and inactive homology models of the class B calcitonin gene-related peptide (CGRP) receptor, and have supported it with site-directed mutagenesis data using 122 CGRP receptor residues and 144 published mutagenesis results on other class B GPCRs. The variation of sequence variability with structure, the analysis of polarity violations, the alignment of group-conserved residues and the mutagenesis results at 27 key positions were particularly informative in distinguishing between the proposed and plausible alternative alignments. Furthermore, we have been able to associate the key molecular features of the class B GPCR signalling machinery with their class A counterparts for the first time. These include the [K/R]KLH motif in intracellular loop 1, [I/L]xxxL and KxxK at the intracellular end of TM5 and TM6, the NPXXY/VAVLY motif on TM7 and small group-conserved residues in TM1, TM2, TM3 and TM7. The equivalent of the class A DRY motif is proposed to involve Arg 2.39 , His 2.43 and Glu 3.46 , which makes a polar lock with T 6.37 . These alignments and models provide useful tools for understanding class B GPCR function.

Role of helix 8 in G protein-coupled receptors based on structure–function studies on the type 1 angiotensin receptor

2009 ◽  
Vol 302 (2) ◽  
pp. 118-127 ◽  
Author(s):  
John Huynh ◽  
Walter Glen Thomas ◽  
Marie-Isabel Aguilar ◽  
Leonard Keith Pattenden
Keyword(s):  
Structure Function ◽  
G Protein ◽  
G Protein Coupled Receptors ◽  
Angiotensin Receptor ◽  
G Protein Coupled

Bioinformatics and type II G-protein-coupled receptors

2002 ◽  
Vol 30 (4) ◽  
pp. 473-479 ◽  
Author(s):  
S. M. Foord ◽  
S. Jupe ◽  
J. Holbrook
Keyword(s):  
Parathyroid Hormone ◽  
G Protein ◽  
Sequence Homology ◽  
G Protein Coupled Receptors ◽  
Type Ii ◽  
Corticotrophin Releasing Factor ◽  
Large N ◽  
G Protein Coupled ◽  
7Tm Receptors

The best known family B, or Type II, G-protein-coupled receptors (GPCRs) recognize peptides as ligands. The receptors for corticotrophin-releasing factor, parathyroid hormone and secretin typify this group. However, there are only 15 such GPCRs. Many other receptors share sequence homology and have been assigned to this family. The ten ‘Frizzled’ and one ‘Smoothened’ receptors show the lowest sequence homology and are not necessarily G-protein coupled. Drosophila genetics have enabled our understanding of their biology. In contrast, relatively little is known about the largest group with family B, the 33 ‘large amino termini’ or large N-terminal family B seven-transmembrane (LNB 7TM) receptors. This review highlights the similarities found between family B receptors and provides a classification of LNB 7TM receptors.

scholarly journals Contribution of AT1R mechanoactivation to the arterial myogenic response and its regulation by RGS5 protein in skeletal muscle arterioles

2015 ◽  
Author(s):  
◽  
Kwangseok Hong
Keyword(s):  
G Protein ◽  
Mechanical Stimulus ◽  
G Protein Coupled Receptors ◽  
G Protein Signaling ◽  
Myogenic Response ◽  
Protein Signaling ◽  
Regulatory Molecule ◽  
Cytoskeleton Reorganization ◽  
G Protein Coupled

Although intracellular mechanisms underlying the arteriolar myogenic response have been well-defined, the mechanotransduction events transducing the mechanical stimulus remain unclear. Recently, ligand-independent activation of G protein-coupled receptors (in particular, the angiotensin II type 1 receptor; AT1R) has been suggested to play a major role in vascular smooth muscle mechanotransduction, thereby contributing to myogenic constriction. However, the downstream pathways following ligand-independent activation of the AT1R have not been clearly elucidated. Our studies provide pharmacological evidence that the mechanically activated AT1R generates diacylglycerol which in turn activates PKC that subsequently induces actin cytoskeleton reorganization for myogenic constriction. In terms of physiological roles, the arterial myogenic response acts to generate vascular tone, prevent capillaries from being damaged, and reduce edema due to high capillary hydrostatic pressure. Thus, an exaggerated AT1R-mediated myogenic constriction could conceivably contribute to vascular disorders. As a result, small arteries likely exhibit negative feedback regulatory mechanisms to prevent such an exaggerated myogenic response. In regard to this, we discovered that ligand-dependent or-independent activation of the AT1R causes trafficking of an important regulatory molecule, RGS5 (Regulators of G protein Signaling) protein, which may modulate Ang II or myogenic-mediated constriction by terminating Gq/11 protein-dependent signaling.

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 Multiplexed analysis of the secretin-like GPCR-RAMP interactome

2019 ◽  
Vol 5 (9) ◽  
pp. eaaw2778 ◽  
Author(s):  
Emily Lorenzen ◽  
Tea Dodig-Crnković ◽  
Ilana B. Kotliar ◽  
Elisa Pin ◽  
Emilie Ceraudo ◽  
...  
Keyword(s):  
Membrane Protein ◽  
G Protein ◽  
Chemokine Receptors ◽  
G Protein Coupled Receptors ◽  
Orphan Receptors ◽  
Native Proteins ◽  
Receptor Activity Modifying Proteins ◽  
G Protein Coupled ◽  
Suspension Bead Array ◽  
Multiplexed Analysis

Receptor activity–modifying proteins (RAMPs) have been shown to modulate the functions of several G protein–coupled receptors (GPCRs), but potential direct interactions among the three known RAMPs and hundreds of GPCRs have never been investigated. Focusing mainly on the secretin-like family of GPCRs, we engineered epitope-tagged GPCRs and RAMPs, and developed a multiplexed suspension bead array (SBA) immunoassay to detect GPCR-RAMP complexes from detergent-solubilized lysates. Using 64 antibodies raised against the native proteins and 4 antibodies targeting the epitope tags, we mapped the interactions among 23 GPCRs and 3 RAMPs. We validated nearly all previously reported secretin-like GPCR-RAMP interactions, and also found previously unidentified RAMP interactions with additional secretin-like GPCRs, chemokine receptors, and orphan receptors. The results provide a complete interactome of secretin-like GPCRs with RAMPs. The SBA strategy will be useful to search for additional GPCR-RAMP complexes and other interacting membrane protein pairs in cell lines and tissues.

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