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Apelin Receptor

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Bo Bai – One of the best experts on this subject based on the ideXlab platform.

  • Temporal Expression of Apelin/Apelin Receptor in Ischemic Stroke and its Therapeutic Potential.
    Frontiers in molecular neuroscience, 2017
    Co-Authors: Xin Wang, Xuan Zhou, Baohua Cheng, Bo Bai

    Abstract:

    Stroke is one of the leading causes of death and disability worldwide, and ischemic stroke accounts for approximately 87% of cases. Improving post-stroke recovery is a major challenge in stroke treatment. Accumulated evidence indicates that the Apelinergic system, consisting of Apelin and Apelin Receptor (APLNR), is temporally dysregulated in ischemic stroke. Moreover, the Apelinergic system plays a pivotal role in post-stroke recovery by inhibiting neuronal apoptosis and facilitating angiogenesis through various molecular pathways. In this review article, we summarize the temporal expression of Apelin and APLNR in ischemic stroke and the mechanisms of their dysregulation. In addition, the protective role of the Apelinergic system in ischemic stroke and the underlying mechanisms of its protective effects are discussed. Furthermore, critical issues in activating the Apelinergic system as a potential therapy will also be discussed. The aim of this review article is to shed light on exploiting the activation of the Apelinergic system to treat ischemic stroke.

  • temporal expression of Apelin Apelin Receptor in ischemic stroke and its therapeutic potential
    Frontiers in Molecular Neuroscience, 2017
    Co-Authors: Xin Wang, Xuan Zhou, Baohua Cheng, Bo Bai

    Abstract:

    Stroke is one of the leading causes of death and disability worldwide, and ischemic stroke accounts for approximately 87% of cases. Improving post-stroke recovery is a major challenge in stroke treatment. Accumulated evidence indicates that the Apelinergic system, consisting of Apelin and Apelin Receptor (APLNR), is temporally dysregulated in ischemic stroke. Moreover, the Apelinergic system plays a pivotal role in post-stroke recovery by inhibiting neuronal apoptosis and facilitating angiogenesis through various molecular pathways. In this review article, we summarize the temporal expression of Apelin and APLNR in ischemic stroke and the mechanisms of their dysregulation. In addition, the protective role of the Apelinergic system in ischemic stroke and the underlying mechanisms of its protective effects are discussed. Furthermore, critical issues in activating the Apelinergic system as a potential therapy will also be discussed. The aim of this review article is to shed light on exploiting the activation of the Apelinergic system to treat ischemic stroke.

  • Apelin Receptor homodimer-oligomers revealed by single-molecule imaging and novel G protein-dependent signaling
    Scientific reports, 2017
    Co-Authors: Xin Cai, Bo Bai, Rumin Zhang, Chunmei Wang, Jing Chen

    Abstract:

    The Apelin Receptor (APJ) belongs to family A of the G protein-coupled Receptors (GPCRs) and is a potential pharmacotherapeutic target for heart failure, hypertension, and other cardiovascular diseases. There is evidence APJ heterodimerizes with other GPCRs; however, the existence of APJ homodimers and oligomers remains to be investigated. Here, we measured APJ monomer-homodimer-oligomer interconversion by monitoring APJ dynamically on cells and compared their proportions, spatial arrangement, and mobility using total internal reflection fluorescence microscopy, resonance energy transfer, and proximity biotinylation. In cells with

Anthony P. Davenport – One of the best experts on this subject based on the ideXlab platform.

  • international union of basic and clinical pharmacology cvii structure and pharmacology of the Apelin Receptor with a recommendation that elabela toddler is a second endogenous peptide ligand
    Pharmacological Reviews, 2019
    Co-Authors: Cai Read, Robyn Macrae, Duuamene Nyimanu, Janet J. Maguire, Peiran Yang, Thomas L. Williams, David J Huggins, Petra Sulentic, Robert C Glen, Anthony P. Davenport

    Abstract:

    The predicted protein encoded by the APJ gene discovered in 1993 was originally classified as a class A G protein-coupled orphan Receptor but was subsequently paired with a novel peptide ligand, Apelin-36 in 1998. Substantial research identified a family of shorter peptides activating the Apelin Receptor, including Apelin-17, Apelin-13, and [Pyr1]Apelin-13, with the latter peptide predominating in human plasma and cardiovascular system. A range of pharmacological tools have been developed, including radiolabeled ligands, analogs with improved plasma stability, peptides, and small molecules including biased agonists and antagonists, leading to the recommendation that the APJ gene be renamed APLNR and encode the Apelin Receptor protein. Recently, a second endogenous ligand has been identified and called Elabela/Toddler, a 54-amino acid peptide originally identified in the genomes of fish and humans but misclassified as noncoding. This precursor is also able to be cleaved to shorter sequences (32, 21, and 11 amino acids), and all are able to activate the Apelin Receptor and are blocked by Apelin Receptor antagonists. This review summarizes the pharmacology of these ligands and the Apelin Receptor, highlights the emerging physiologic and pathophysiological roles in a number of diseases, and recommends that Elabela/Toddler is a second endogenous peptide ligand of the Apelin Receptor protein.

  • Apelin Receptor (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database
    IUPHAR BPS Guide to Pharmacology CITE, 2019
    Co-Authors: Anthony P. Davenport, Duuamene Nyimanu, Janet J. Maguire, Matthias J. Kleinz, Thomas L. Williams, Robyn G. C. Macrae, Peiran Yang

    Abstract:

    The Apelin Receptor (nomenclature as agreed by the NC-IUPHAR Subcommittee on the Apelin Receptor [68]) responds to Apelin, a 36 amino-acid peptide derived initially from bovine stomach. Apelin-36, Apelin-13 and [Pyr1]Apelin-13 are the predominant endogenous ligands which are cleaved from a 77 amino-acid precursor peptide (APLN, Q9ULZ1) by a so far unidentified enzymatic pathway [80]. A second family of peptides discovered independently and named Elabela [11] or Toddler, that has little sequence similarity to Apelin, is present, and functional at the Apelin Receptor in the adult cardiovascular system [87, 67]. Structure-activity relationship Elabela analogues have been described [61].

  • Apelin-36-[L28A] and Apelin-36-[L28C(30kDa-PEG)] peptides that improve diet induced obesity are G protein biased ligands at the Apelin Receptor.
    Peptides, 2019
    Co-Authors: Duuamene Nyimanu, Rhoda E. Kuc, Janet J. Maguire, Thomas L. Williams, Maria Bednarek, Philip D Ambery, Lutz Jermutus, Anthony P. Davenport

    Abstract:

    Abstract Background Apelin signalling pathways have important cardiovascular and metabolic functions. Recently, Apelin-36-[L28A] and Apelin-36-[L28C(30kDa-PEG)], were reported to function independent of the Apelin Receptor in vivo to produce beneficial metabolic effects without modulating blood pressure. We aimed to show that these peptides bound to the Apelin Receptor and to further characterise their pharmacology in vitro at the human Apelin Receptor. Methods [Pyr1]Apelin-13 saturation binding experiments and competition binding experiments were performed in rat and human heart homogenates using [125I]Apelin-13 (0.1 nM), and/or increasing concentrations of Apelin-36, Apelin-36-[L28A] and Apelin-36-[L28C(30kDa-PEG)] (50pM-100μM). Apelin-36 and its analogues Apelin-36-[F36A], Apelin-36-[L28A], Apelin-36-[L28C(30kDa-PEG)], Apelin-36-[A28 A13] and [40kDa-PEG]-Apelin-36 were tested in forskolin-induced cAMP inhibition and β–arrestin assays in CHO-K1 cells heterologously expressing the human Apelin Receptor. Bias signaling was quantified using the operational model for bias. Results In both species, [Pyr1]Apelin-13 had comparable subnanomolar affinity and the Apelin Receptor density was similar. Apelin-36, Apelin-36-[L28A] and Apelin-36-[L28C(30kDa-PEG)] competed for binding of [125I]Apelin-13 with nanomolar affinities. Apelin-36-[L28A] and Apelin-36-[L28C(30kDa-PEG)] inhibited forskolin-induced cAMP release, with nanomolar potencies but they were less potent compared to Apelin-36 at recruiting β-arrestin. Bias analysis suggested that these peptides were G protein biased. Additionally, [40kDa-PEG]-Apelin-36 and Apelin-36-[F36A] retained nanomolar potencies in both cAMP and β-arrestin assays whilst Apelin-36-[A13 A28] exhibited a similar profile to Apelin-36-[L28C(30kDa-PEG)] in the β–arrestin assay but was more potent in the cAMP assay. Conclusions Apelin-36-[L28A] and Apelin-36-[L28C(30kDa-PEG)] are G protein biased ligands of the Apelin Receptor, suggesting that the Apelin Receptor is an important therapeutic target in metabolic diseases.

Jan K Rainey – One of the best experts on this subject based on the ideXlab platform.

  • Structure, amphipathy, and topology of the membrane-proximal helix 8 influence Apelin Receptor plasma membrane localization.
    Biochimica et biophysica acta. Biomembranes, 2019
    Co-Authors: Aditya Pandey, Muzaddid Sarker, Xiang-qin Liu, Danielle M. Leblanc, Hirendrasinh B. Parmar, Trần Thanh Tâm Phạm, Roy Duncan, Jan K Rainey

    Abstract:

    Abstract G-protein coupled Receptors (GPCRs) typically have an amphipathic helix (“helix 8”) immediately C-terminal to the transmembrane helical bundle. To date, a number of functional roles have been associated with GPCR helix 8 segments, but structure-function analysis for this region remains limited. Here, we examine helix 8 of the Apelin Receptor (AR or APJ), a class A GPCR with wide physiological and pathophysiological relevance. The 71 residue C-terminal tail of the AR is primarily intrinsically disordered, with a detergent micelle-induced increase in helical character. This helicity was localized to the helix 8 region, in good agreement with the recent AR crystal structure. A series of helix 8 mutants were made to reduce helicity, remove amphipathy, or flip the hydrophobic and hydrophilic faces. Each mutant AR was tested both biophysically, in the isolated C-terminal tail, and functionally in HEK 293 T cells, for full-length AR. In all instances, micelle interactions were maintained, and steady-state AR expression was efficient. However, removal of amphipathy or helical character led to a significant decrease in cell surface localization. Flipping of helix 8 amphipathic topology restored cell surface localization to some degree, but still was significantly reduced relative to wild-type. Structural integrity, amphipathy to drive membrane association, and correct topology of helix 8 membrane association all thus appear important for cell surface localization of the AR. This behavior correlates well to GPCR C-terminal tail sequence motifs, implying that these serve to specify key topological features of helix 8 and its proximity to the transmembrane domain.

  • Bioactivity of the putative Apelin proprotein expands the repertoire of Apelin Receptor ligands.
    Biochimica et biophysica acta. General subjects, 2017
    Co-Authors: Kyungsoo Shin, Nigel A. Chapman, Denis J. Dupré, Aditya Pandey, Muzaddid Sarker, Calem Kenward, Shuya K. Huang, Nathan Weatherbee-martin, Jan K Rainey

    Abstract:

    Abstract Background Apelin is a peptide ligand for a class A G-protein coupled Receptor called the Apelin Receptor (AR or APJ) that regulates angiogenesis, the adipoinsular axis, and cardiovascular functions. Apelin has been shown to be bioactive as 13, 17, and 36 amino acid isoforms, C-terminal fragments of the putatively inactive 55-residue proprotein (proApelin or Apelin-55). Although intracellular proprotein processing has been proposed, isolation of Apelin-55 from colostrum and milk demonstrates potential for secretion prior to processing and the possibility of proApelin-AR interaction. Methods Apelin isoform activity and potency were compared by an In-Cell Western™ assay for ERK phosphorylation using a stably AR-transfected HEK293A cell line. Conformational comparison of Apelin isoforms was carried out by circular dichroism and heteronuclear solution-state nuclear magnetic resonance spectroscopy. Results Apelin-55 is shown to activate the AR, with similar maximum ERK phophorylation response and potency to the shorter isoforms except for Apelin-13, which exhibited a greater potency. Correlating to this shared activity, highly similar conformations are exhibited in all Apelin isoforms for the shared C-terminal region responsible for Receptor binding and activation. Conclusions AR activation by all Apelin isoforms likely hinges upon shared conformation and dynamics in the C-terminus, with Apelin-55 providing an alternative bioactive isoform despite the addition of 19 N-terminal residues relative to Apelin-36. General significance Beyond providing novel insight into the physiology of this system, re-annotation of proApelin to the bioactive Apelin-55 isoform adds to the molecular toolkit for dissection of Apelin-AR interactions and expands the repertoire of therapeutic targets for the Apelinergic system.

  • The Apelin Receptor: physiology, pathology, cell signalling, and ligand modulation of a peptide-activated class A GPCR.
    Biochemistry and Cell Biology, 2014
    Co-Authors: Nigel A. Chapman, Denis J. Dupré, Jan K Rainey

    Abstract:

    The Apelin Receptor (AR or APJ) is a class A (rhodopsin-like) G-protein-coupled Receptor with wide distribution throughout the human body. Activation of the AR by its cognate peptide ligand, Apelin, induces diverse physiological effects including vasoconstriction and dilation, strengthening of heart muscle contractility, angiogenesis, and regulation of energy metabolism and fluid homeostasis. Recently, another endogenous peptidic activator of the AR, Toddler/ELABELA, was identified as having a crucial role in zebrafish (Danio rerio) embryonic development. The AR is also implicated in pathologies including cardiovascular disease, diabetes, obesity, and cancer, making it a promising therapeutic target. Despite its established importance, the precise roles of AR signalling remain poorly understood. Moreover, little is known about the mechanisms of peptide–AR activation. Additional complexity arises from modulation of the AR by 2 endogenous peptide ligands, both with multiple bioactive isoforms of variable le…