Proadrenomedullin N-terminal peptide and cortistatin activation of MrgX2 receptor is based on a common structural motif

doi:10.1016/j.ejphar.2005.07.001

European Journal of Pharmacology

Volume 519, Issues 1–2, 5 September 2005, Pages 191-193

https://doi.org/10.1016/j.ejphar.2005.07.001 Get rights and content

Abstract

The G protein-coupled receptor MrgX2 belongs to the large family of the Mas-related genes or sensory neuron-specific G protein-coupled receptors. The MrgX2 receptor has been shown to be activated by the peptides cortistatin and proadrenomedullin N-terminal peptides (PAMP). Here we investigated the structure activity relationship of PAMP and identified key structural features that are shared with cortistatin and might explain why two apparently unrelated peptides are able to activate a single G protein-coupled receptor.

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Acknowledgement

This work was supported by research grants from the National Institute of Health (MH60231, DK63001 and DK070619 to O.C. and MH68396 to H.P.N.).

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Mast cells play a pivotal role in initiating and directing host's immune response. They reside in tissues that primarily interface with the external environment. Activated mast cells respond to environmental cues throughout acute and chronic inflammation through releasing immune mediators via rapid degranulation, or long-term de novo expression. Mast cell activation results in the rapid release of a variety of unique enzymes and reactive oxygen species. Furthermore, the increased density of mast cell unique receptors like mas related G protein-coupled receptor X2 also characterizes the inflamed tissues. The presence of these molecules (either released mediators or surface receptors) are particular to the sites of active inflammation, and are a result of mast cell activation. Herein, the molecular design principles for capitalizing on these novel mast cell properties is discussed with the goal of manipulating localized inflammation.
Mast cells are immune regulating cells that play a crucial role in both innate and adaptive immune responses. The activation of mast cells causes the release of multiple unique profiles of biomolecules, which are specific to both tissue and disease. These unique characteristics are tightly regulated and afford a localized stimulus for targeting inflammatory diseases. Herein, these important mast cell attributes are discussed in the frame of highlighting strategies for the design of bioresponsive functional materials to target regions of inflammations.
MAS-related G protein-coupled receptors X (MRGPRX): Orphan GPCRs with potential as targets for future drugs
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Citation Excerpt :
It is still classified as an orphan receptor, despite having a plethora of agonists including small molecules, peptides, and proteins. This receptor breaches the dogma of receptor-ligand specificity since it is activated by a variety of structurally and functionally diverse ligands (Grimes et al., 2019; Kashem et al., 2011; Lansu et al., 2017; McNeil et al., 2015; Nothacker et al., 2005; Tatemoto et al., 2006; Zhang et al., 2005). MRGPRX2 agonists can be divided into two main classes: peptides (Table 8) and non-peptidic agonists (Table 9).
MAS-related G protein-coupled receptors (GPCRs) of subfamily X, designated MRGPRX, are primate-specific orphan receptors that belong to the δ-branch of rhodopsin-like, class A GPCRs. Four distinct subtypes exist, MRGPRX1, -2, -3, and -4, MRGPRX2 having the lowest degree of similarity with the others. Due to their expression on sensory neurons and immune cells, and their roles in pain perception and transmission, itch, inflammation, immune defense, pseudo-allergic reactions, wound healing, and possibly cancer, they have recently attracted much attention as novel drug targets. In particular MRGPRX2 was identified as an important mast cell receptor, responsible for anaphylactoid drug reactions and involved in skin and mucosal diseases, e.g. urticaria, atopic dermatitis, rosacea, and allergic rhinitis. A major hurdle has been the lack of animal models for studying these primate-specific receptors. However, recently humanized mice have been created. Moreover, a mouse ortholog of MRGPRX2, MRGPRB2, was identified, both receptors having a certain degree of similarity. MRGPRX1 and -2 can be activated by various peptides and small (partly peptidomimetic) molecules. MRGPRX2 is additionally activated by a very broad range of basic molecules, positively charged at physiologic pH value of 7.4, including many drugs. MRGPRX4 is activated by small acidic molecules including bile acids. For MRGPRX3, no ligands have been reported yet. Antagonists with reasonable potency and selectivity have been described for MRGPRX1, and few antagonists also for MRGPRX2, but not for the other subtypes. The recent elucidation of cryogenic electron microscopy structures of MRGPRX2 and -4 is expected to facilitate and advance drug development for these receptors. Currently, research on MRGPRX is still in its infancy, and exciting discoveries can be awaited. These receptors have great potential as future drug targets.
Identification of short peptide sequences that activate human mast cells via Mas-related G-protein coupled receptor member X2
2021, Acta Biomaterialia
Citation Excerpt :
YKKKY with the less hydrophobic tyrosine at 61 ± 1% was less than PAMP-12, WKKKW, and FKKKF. Similarity between ligand structures that activate MRGPRX2 expressing mast cells have been discussed, including between PAMP-12 and cortisatin-14 [17,24]. MRGPRX2 is known to consist of a large number of hydrophobic and negatively charged Glu164 and Asp184 residues that contribute to ligand binding.
Peptide based therapeutics are desirable owing to their high biological specificity. However, a number of these fail in clinical testing due to an adverse inflammatory response. Mast cells play a key role in directing the host response to drugs and related products. Although the role of FcεRI receptor is well known, Mas-related G-protein coupled receptor X2 (MRGPRX2) binding of endogenous peptides, and drugs will activate mast cells independent of FcεRI. Identifying peptides that activate mast cells through MRGPRX2, and their respective activation potency, can be used to reduce the failure rate of peptide therapeutics at clinical trial. Moreover, it will allow for peptide design where mast cell activation is actually desired. It was found that FRKKW and WNKWAL are two motifs that activate human LAD2 cells similar to PAMP-12 controls. Peptide activators of MRGPRX2 could be reduced to X_a-(Y)_{(n ≥ 3)}-X_b where: X_a is an aromatic residue; X_b is a hydrophobic residue; and Y is a minimum 3 residue long sequence, containing a minimum of one positively charged residue with the remainder being uncharged residues. Artificial peptides WKKKW and FKKKF were constructed to test this structural functionality and were similar to PAMP-12 controls. Peptides with different activation potentials were found where FRKKW = WKKKW = FKKKF > PAMP-12 = WNKWAL > YKKKY > FRKKANKWALSR = FRKKWNKAALSR > KWKWK > FRKK = WNKWA > KYKYK > NKWALSR = YKKY = WNK. These sequences should be considered when designing peptide-based therapeutics.
Mast cells release immune regulating molecules upon activation that direct host's immune response. MRGPRX2 receptor provides an alternate pathway for mast cell activation that is independent of FcεRI receptor. It is thought that mast cell activation through MRGPRX2 plays a critical role in high failure rates of drugs in clinical trials. Identifying peptide sequences that activate mast cells through MRGPRX2 can serve two important purposes, namely, sequences to avoid when designing peptide therapeutics, and artificial peptides with different activation potentials for mast cells. Herein, we have identified a general amino acid sequence that induces mast cell activation through MRGPRX2. Furthermore, by modulating the identified sequence, artificial peptides have been designed which activate mast cells by varying degrees for therapeutic applications.
Activation of Mast-Cell-Expressed Mas-Related G-Protein-Coupled Receptors Drives Non-histaminergic Itch
2019, Immunity
Citation Excerpt :
Canonically, mast cell activation is understood to result from antigen binding to immunoglobulin E (IgE) antibody and crosslinking of the high-affinity IgE receptor, Fc epsilon RI (FcεRI). More recently, members of the Mas-related family of G-protein-coupled receptors (Mrgprs), Mrgprb2 in mice and MRGPRX2 in humans, have been identified as mast cell-expressed G-protein-coupled receptors (Kamohara et al., 2005; McNeil et al., 2015; Nothacker et al., 2005; Robas et al., 2003; Subramanian et al., 2011). Murine Mrgprb2 and human MRGPRX2 are activated by basic secretagogues, a class of positively charged molecules known to activate mast cells through a non-IgE mechanism (Galli and Tsai, 2012; Meixiong and Dong, 2017).
Classical itch studies have focused on immunoglobulin E (IgE)-mediated mast cell activation and histamine release. Recently, members of the Mas-related G-protein-coupled receptor (Mrgpr) family have been identified as mast cell receptors, but their role in itch is unclear. Here, we report that mast cell activation via Mrgprb2 evoked non-histaminergic itch in mice independently of the IgE-Fc epsilon RI (FcεRI)-histamine axis. Compared with IgE-FcεRI stimulation, Mrgprb2 activation of mast cells was distinct in both released substances (histamine, serotonin, and tryptase) and the pattern of activated itch-sensory neurons. Mrgprb2 deficiency decreased itch in multiple preclinical models of allergic contact dermatitis (ACD), a pruritic inflammatory skin disorder, and both mast cell number and PAMP1-20 concentrations (agonist of the human Mrgprb2 homolog, MRGPRX2) were increased in human ACD skin. These findings suggest that this pathway may represent a therapeutic target for treating ACD and mast-cell-associated itch disorders in which antihistamines are ineffective.
Cortistatin modulates the expression and release of corticotrophin releasing hormone in rat brain. Comparison with somatostatin and octreotide
2012, Peptides
Citation Excerpt :
Putative CST receptors are the Mas-related gene X2 (MrgX2) receptor and the GHS-R1a ghrelin receptor [1,15,35]. MrgX2 receptor is not expressed in the cerebral cortex, where CST expression is most abundant [35]; MrgX2 appears to be non-specific to CST, since it acts as a receptor for pro-adrenomedullin and related peptides [31] as well. The possible role GHS-R1a as CST receptor has also been questioned.
Cortistatin (CST) is an endogenous neuropeptide characterized by remarkable structural and functional resemblance to somatostatin (SST), both peptides sharing the ability to bind and activate all five SST receptor subtypes. Evidence is also available showing that CST exerts biological activities independently from SST, perhaps via the activation of specific receptors that remain to be fully characterized at present. Here we have investigated the effects of CST on the gene expression and release of corticotrophin releasing hormone (CRH) from rat hypothalamic and hippocampal explants; moreover, we compared the effects of CST with those of SST and octreotide (OCT) in these models. We found that: (i) CST inhibits the expression and release of CRH from rat hypothalamic and hippocampal explants under basal conditions as well as after CRH stimulation by well known secretagogues; (ii) SST does not modify basal CRH secretion from the hypothalamus or the hippocampus, while it is able to reduce KCl-stimulated CRH release from both brain areas; (iii) OCT inhibits both basal and KCl-induced CRH secretion from rat hypothalamic explants, while it has no effect on CRH release from the hippocampus, either under basal conditions or after stimulation by high K⁺ concentrations; (iv) at variance with CST; SST and OCT have not effect whatsoever on veratridine-induced CRH release from the hypothalamus. In conclusion the present findings provide in vitro evidence in support of the hypothesis that CST plays a role in the regulation of endocrine adaptive responses to stress.
The role of cortistatin in the human immune system
2008, Molecular and Cellular Endocrinology
Cortistatin (CST) is a recently described neuropeptide that shares high homology with somatostatin (somatotropin release-inhibiting factor, SRIF) and binds with high affinity to all somatostatin (sst) receptor subtypes. CST is currently known to have a widespread distribution in many human organs including the immune system. The activities specific to CST may be partially attributable to its binding to the growth hormone secretagogue (GHS)-receptor (GHS-R) and the orphan G-protein-coupled receptor MrgX2. Human immune cells produce CST, whereas macrophage lineage and activated endothelium express sst2, and human lymphocytes express sst3. The human thymus expresses sst1, 2, 3, MrgX2 and almost all immune cells express GHS-R. Moreover, at this very moment promising research with CST in experimental animal models is being performed. On the basis of these promising results, studies aiming to further evaluate the possibilities of CST as a therapeutic agent in human immune-mediated inflammatory diseases are warranted.

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Rapid communicationProadrenomedullin N-terminal peptide and cortistatin activation of MrgX2 receptor is based on a common structural motif

Abstract

Section snippets

Acknowledgement

Cell

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Brain Res. Brain Res. Rev.

Rapid communication
Proadrenomedullin N-terminal peptide and cortistatin activation of MrgX2 receptor is based on a common structural motif