Elaboration of Mechanisms by Which Distinct Apelin Receptor Bioactivity is Elicited by Endogenous Peptide Ligand Processing

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 length and distribution. The various apelin and Toddler/ELABELA isoforms may also produce distinct cellular effects. Further complexity arises through formation of functionally distinct heterodimers between the AR and other G-protein-coupled receptors. This minireview outlines key (patho)physiological actions of the AR, addresses what is known about signal transduction downstream of AR activation, and concludes by discussing unique properties of the endogenous peptidic ligands of the AR.

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Endogenous peptide ligand–receptor systems for diverse signaling networks in plants

Current Opinion in Plant Biology ◽

10.1016/j.pbi.2014.07.011 ◽

2014 ◽

Vol 21 ◽

pp. 140-146 ◽

Cited By ~ 21

Author(s):

Satoshi Endo ◽

Shigeyuki Betsuyaku ◽

Hiroo Fukuda

Keyword(s):

Signaling Networks ◽

Peptide Ligand ◽

Endogenous Peptide

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Recognition of GPCRs by Peptide Ligands and Membrane Compartments theory: Structural Studies of Endogenous Peptide Hormones in Membrane Environment

Bioscience Reports ◽

10.1007/s10540-006-9014-z ◽

2006 ◽

Vol 26 (2) ◽

pp. 131-158 ◽

Cited By ~ 22

Author(s):

Ramasubbu Sankararamakrishnan

Keyword(s):

Drug Design ◽

Experimental Studies ◽

Peptide Hormones ◽

Peptide Ligands ◽

Rational Drug Design ◽

Peptide Ligand ◽

Diverse Range ◽

Endogenous Peptide ◽

Rational Drug ◽

Membrane Compartments

One of the largest family of cell surface proteins, G-protein coupled receptors (GPCRs) regulate virtually all known physiological processes in mammals. With seven transmembrane segments, they respond to diverse range of extracellular stimuli and represent a major class of drug targets. Peptidergic GPCRs use endogenous peptides as ligands. To understand the mechanism of GPCR activation and rational drug design, knowledge of three-dimensional structure of receptor–ligand complex is important. The endogenous peptide hormones are often short, flexible and completely disordered in aqueous solution. According to “Membrane Compartments Theory”, the flexible peptide binds to the membrane in the first step before it recognizes its receptor and the membrane-induced conformation is postulated to bind to the receptor in the second step. Structures of several peptide hormones have been determined in membrane-mimetic medium. In these studies, micelles, reverse micelles and bicelles have been used to mimic the cell membrane environment. Recently, conformations of two peptide hormones have also been studied in receptor-bound form. Membrane environment induces stable secondary structures in flexible peptide ligands and membrane-induced peptide structures have been correlated with their bioactivity. Results of site-directed mutagenesis, spectroscopy and other experimental studies along with the conformations determined in membrane medium have been used to interpret the role of individual residues in the peptide ligand. Structural differences of membrane-bound peptides that belong to the same family but differ in selectivity are likely to explain the mechanism of receptor selectivity and specificity of the ligands. Knowledge of peptide 3D structures in membrane environment has potential applications in rational drug design.

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Venous dilator effect of apelin, an endogenous peptide ligand for the orphan APJ receptor, in conscious rats

European Journal of Pharmacology ◽

10.1016/s0014-2999(03)01821-1 ◽

2003 ◽

Vol 470 (3) ◽

pp. 171-175 ◽

Cited By ~ 123

Author(s):

Xing Cheng ◽

Xiao Shuo Cheng ◽

Catherine C.Y. Pang

Keyword(s):

Peptide Ligand ◽

Conscious Rats ◽

Endogenous Peptide

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An Endogenous Peptide Ligand for the PCP/σ-Opiod Receptor

Neural and Endocrine Peptides and Receptors ◽

10.1007/978-1-4684-5152-8_1 ◽

1986 ◽

pp. 3-13

Author(s):

Patricia C. Contreras ◽

Debora A. Dimaggio ◽

Thomas L. O’Donohue ◽

Rémi Quirion

Keyword(s):

Peptide Ligand ◽

Endogenous Peptide

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Isolation and Characterization of a Novel Endogenous Peptide Ligand for the Human APJ Receptor

Biochemical and Biophysical Research Communications ◽

10.1006/bbrc.1998.9489 ◽

1998 ◽

Vol 251 (2) ◽

pp. 471-476 ◽

Cited By ~ 970

Author(s):

Kazuhiko Tatemoto ◽

Masaki Hosoya ◽

Yugo Habata ◽

Ryo Fujii ◽

Tadao Kakegawa ◽

...

Keyword(s):

Peptide Ligand ◽

Endogenous Peptide ◽

Isolation And Characterization

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Modulation of T cell development by an endogenous altered peptide ligand.

Journal of Experimental Medicine ◽

10.1084/jem.181.2.805 ◽

1995 ◽

Vol 181 (2) ◽

pp. 805-810 ◽

Cited By ~ 30

Author(s):

B L Hsu ◽

B D Evavold ◽

P M Allen

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Development ◽

Cell Development ◽

Peptide Ligand ◽

Altered Peptide Ligand ◽

High Avidity ◽

Endogenous Peptide ◽

T Cell Clone ◽

The Impact

T cells potentially encounter numerous endogenous peptides during selection in the thymus and in the periphery. We examined the impact of an endogenous peptide on in vivo T cell development, using a TCR transgenic mouse model based on a hemoglobin-specific T cell clone. In these mice, the transgenic beta chains paired with endogenous alpha chains. This led to a serendipitous primary reactivity to Ser69 peptide, an altered peptide ligand of the Hbd (64-76) epitope of the parent clone. Two Ser69-reactive T cell populations were identified. A smaller population of the Ser69-reactive T cells responded both to Ser69 and Hbd (64-76). A majority reacted only to Ser69, and not to Hbd(64-76); in fact, Hbd(64-76) was a specific TCR antagonist for these Ser69-only-reactive T cells. Thus, in this unique experimental system, Ser69 became an agonist, and Hbd (64-76) was an antagonist. Endogenous presentation of the antagonist ligand in the thymus selectively eliminated the high-avidity cells, while sparing low-avidity cells in the Ser69-reactive T cell repertoire. These results highlight how specificity guides developing T cells through a network of ligands and indicate that the endogenous peptide pool has a profound effect on T cell development and repertoire.

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APELIN promotes hematopoiesis from human embryonic stem cells

Blood ◽

10.1182/blood-2011-12-396093 ◽

2012 ◽

Vol 119 (26) ◽

pp. 6243-6254 ◽

Cited By ~ 34

Author(s):

Qing C. Yu ◽

Claire E. Hirst ◽

Magdaline Costa ◽

Elizabeth S. Ng ◽

Jacqueline V. Schiesser ◽

...

Keyword(s):

Stem Cells ◽

Endothelial Cells ◽

Embryonic Stem Cells ◽

Human Embryonic Stem Cells ◽

Transcriptional Profiling ◽

Embryonic Stem ◽

Embryoid Bodies ◽

Peptide Ligand ◽

The Media ◽

Apelin Receptor

Abstract Transcriptional profiling of differentiating human embryonic stem cells (hESCs) revealed that MIXL1-positive mesodermal precursors were enriched for transcripts encoding the G-protein–coupled APELIN receptor (APLNR). APLNR-positive cells, identified by binding of the fluoresceinated peptide ligand, APELIN (APLN), or an anti-APLNR mAb, were found in both posterior mesoderm and anterior mesendoderm populations and were enriched in hemangioblast colony-forming cells (Bl-CFC). The addition of APLN peptide to the media enhanced the growth of embryoid bodies (EBs), increased the expression of hematoendothelial genes in differentiating hESCs, and increased the frequency of Bl-CFCs by up to 10-fold. Furthermore, APLN peptide also synergized with VEGF to promote the growth of hESC-derived endothelial cells. These studies identified APLN as a novel growth factor for hESC-derived hematopoietic and endothelial cells.

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