Receptor Activity-Modifying Proteins (RAMPs): New Insights and Roles

Hay, Debbie L.; Pioszak, Augen A.

doi:10.1146/annurev-pharmtox-010715-103120

Cited by 156 publications

(153 citation statements)

References 104 publications

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“…pA 2 Calculation for Antagonist Potency-pA 2 indicates the negative logarithm of the antagonist concentration that rightshifts the agonist concentration-response curve by 2-fold as a measure of antagonist affinity. We chose 50% of response for pA 2 calculation and used the Gaddum/Schild EC 50 shift equation with Hill and Schild slopes constrained to 1 in Prism 5.0 (GraphPad Software).…”

Section: Methodsmentioning

confidence: 99%

“…Receptor activity-modifying proteins are single-pass transmembrane proteins (RAMP1-3 in humans) that form heteromeric complexes with several G protein-coupled receptors (GPCRs) 2 and thereby regulate their cell-surface expression and pharmacology (1,2). RAMPs are best characterized for their effects on two class B GPCRs, the calcitonin receptor (CTR) and CTR-like receptor (CLR) (3).…”

mentioning

confidence: 99%

“…RAMPs are best characterized for their effects on two class B GPCRs, the calcitonin receptor (CTR) and CTR-like receptor (CLR) (3). CTR/CLR and their complexes with RAMPs give rise to at least seven pharmacologically distinct receptors (not including splice variants) in humans that exhibit unique selectivity profiles for six related calcitonin (CT) family peptide agonists as follows: CT, amylin (Amy), calcitonin gene-related peptides ␣ and ␤ (␣CGRP and ␤CGRP), adrenomedullin (AM), and adrenomedullin2/intermedin (AM2) (2)(3)(4). CLR⅐RAMP1 is the CGRP receptor at which CGRP has greater potency than AM.…”

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Calcitonin and Amylin Receptor Peptide Interaction Mechanisms

Lee

Hay

Pioszak

2016

Journal of Biological Chemistry

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Receptor activity-modifying proteins (RAMP1-3) determine the selectivity of the class B G protein-coupled calcitonin receptor (CTR) and the CTR-like receptor (CLR) for calcitonin (CT), amylin (Amy), calcitonin gene-related peptide (CGRP), and adrenomedullin (AM) peptides. RAMP1/2 alter CLR selectivity for CGRP/AM in part by RAMP1 Trp-84 or RAMP2 Glu-101 contacting the distinct CGRP/AM C-terminal residues. It is unclear whether RAMPs use a similar mechanism to modulate CTR affinity for CT and Amy, analogs of which are therapeutics for bone disorders and diabetes, respectively. Here, we reproduced the peptide selectivity of intact CTR, AMY 1 (CTR⅐ RAMP1), and AMY 2 (CTR⅐RAMP2) receptors using purified CTR extracellular domain (ECD) and tethered RAMP1-and RAMP2-CTR ECD fusion proteins and antagonist peptides. All three proteins bound salmon calcitonin (sCT). Tethering RAMPs to CTR enhanced binding of rAmy, CGRP, and the AMY antagonist AC413. Peptide alanine-scanning mutagenesis and modeling of receptor-bound sCT and AC413 supported a shared non-helical CGRP-like conformation for their TN(T/ V)G motif prior to the C terminus. After this motif, the peptides diverged; the sCT C-terminal Pro was crucial for receptor binding, whereas the AC413/rAmy C-terminal Tyr had little or no influence on binding. Accordingly, mutant RAMP1 W84A-and RAMP2 E101A-CTR ECD retained AC413/rAmy binding. ECD binding and cell-based signaling assays with antagonist sCT/ AC413/rAmy variants with C-terminal residue swaps indicated that the C-terminal sCT/rAmy residue identity affects affinity more than selectivity. rAmy(8 -37) Y37P exhibited enhanced antagonism of AMY 1 while retaining selectivity. These results reveal unexpected differences in how RAMPs determine CTR and CLR peptide selectivity and support the hypothesis that RAMPs allosterically modulate CTR peptide affinity.Receptor activity-modifying proteins are single-pass transmembrane proteins (RAMP1-3 in humans) that form heteromeric complexes with several G protein-coupled receptors (GPCRs) 2 and thereby regulate their cell-surface expression and pharmacology (1, 2). RAMPs are best characterized for their effects on two class B GPCRs, the calcitonin receptor (CTR) and CTR-like receptor (CLR) (3). CTR/CLR and their complexes with RAMPs give rise to at least seven pharmacologically distinct receptors (not including splice variants) in humans that exhibit unique selectivity profiles for six related calcitonin (CT) family peptide agonists as follows: CT, amylin (Amy), calcitonin gene-related peptides ␣ and ␤ (␣CGRP and ␤CGRP), adrenomedullin (AM), and adrenomedullin2/intermedin (AM2) (2-4). CLR⅐RAMP1 is the CGRP receptor at which CGRP has greater potency than AM. CLR⅐RAMP2 and CLR⅐RAMP3 are the AM 1 and AM 2 receptors, respectively, at which AM is more potent than CGRP (1). AM2 activates the CGRP and AM receptors, but is most potent at AM 2 (5). CTR alone is the CT receptor at which CT is more potent than Amy. CTR complexes with RAMP1, -2, or -3 form distinct AMY 1 , AMY 2 , and AMY 3 rec...

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Calcitonin and Amylin Receptor Peptide Interaction Mechanisms

Lee

Hay

Pioszak

2016

Journal of Biological Chemistry

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“…Receptor activity-modifying proteins (RAMPs) change ligand specificity, trafficking, and posttranslational modification of several GPCRs (2)(3)(4). For example, RAMPs facilitates the transport of calcitonin receptor-like receptor (CALCRL) to the plasma membrane (3), and the ligand specificity of the calcitonin receptor is altered in the presence of RAMPs (5,6). Previous bioinformatics studies addressed RAMP structural conformations and the identification of functional residues (7)(8)(9).…”

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confidence: 99%

GPCRs globally coevolved with receptor activity-modifying proteins, RAMPs

Barbash

Lorenzen

Persson

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Receptor activity-modifying proteins (RAMPs) are widely expressed in human tissues and, in some cases, have been shown to affect surface expression or ligand specificity of G-protein-coupled receptors (GPCRs). However, whether RAMP−GPCR interactions are widespread, and the nature of their functional consequences, remains largely unknown. In humans, there are three RAMPs and over 800 expressed GPCRs, making direct experimental approaches challenging. We analyzed relevant genomic data from all currently available sequenced organisms. We discovered that RAMPs and GPCRs tend to have orthologs in the same species and have correlated phylogenetic trees to the same extent, or higher than other interacting protein pairs that play key roles in cellular signaling. In addition, the resulting RAMP−GPCR interaction map suggests that RAMP1 and RAMP3 interact with the same set of GPCRs, which implies functional redundancy. We next analyzed human transcriptomes and found expression correlation for GPCRs and RAMPs. Our results suggest global coevolution of GPCRs and RAMPS and support the hypothesis that GPCRs interact globally with RAMPs in cellular signaling pathways.coevolution | G-protein-coupled receptor | phylogenetic analysis | receptor activity-modifying protein | signal transduction

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“…Abbreviations: AM, adrenomedullin; Amy, amylin; CaSR, calcium sensing receptor; CGRP, calcitonin gene-related peptide; CLR, calcitonin receptor-like receptor; CRF, corticotrophin releasing factor; CRFR1, corticotrophin-releasing factor type 1 receptor; CT of RAMP-GPCR complexes, the range of GPCRs which associate with RAMPs and the consequences of this both for receptor function and also drug development. For fuller treatment, readers are referred to other reviews [3,4].…”

Section: Introductionmentioning

confidence: 99%

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

Hay

Walker

Gingell

et al. 2016

Biochemical Society Transactions

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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.

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Receptor Activity-Modifying Proteins (RAMPs): New Insights and Roles

Cited by 156 publications

References 104 publications

Calcitonin and Amylin Receptor Peptide Interaction Mechanisms

Calcitonin and Amylin Receptor Peptide Interaction Mechanisms

GPCRs globally coevolved with receptor activity-modifying proteins, RAMPs

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

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