Apelin, a New Enteric Peptide: Localization in the Gastrointestinal Tract, Ontogeny, and Stimulation of Gastric Cell Proliferation and of Cholecystokinin Secretion

Wang, Guiyun; Anini, Younès; Wei, Wei; Xiang, Qi; O’Carroll, Anne Marie; Mochizuki, Tohru; Wang, Hui Quin; Hellmich, Mark R.; Englander, Ella W.; Greeley, George H.

doi:10.1210/en.2003-1116

Cited by 166 publications

(151 citation statements)

References 24 publications

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“…Nevertheless, it should be underlined that the activation of transduction cascades by apelin-(65-77) has also been described in other cell types as well as in isolated organs (19,24,30). As we recently demonstrated that the apelin receptor is expressed by HUVEC (24), we decided to address the question of the physiological relevance of the activation and regulation of these effectors by apelin fragments in these cells.…”

Section: Regulation Of Intracellular Effectors By Apelin Fragments Anmentioning

confidence: 98%

The Apelin Receptor Is Coupled to Gi1 or Gi2 Protein and Is Differentially Desensitized by Apelin Fragments

Masri¹,

Morin

Pedebernade

et al. 2006

Journal of Biological Chemistry

141

113

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The apelin receptor is a G protein-coupled receptor to which two ligand fragments, apelin-(65-77) and apelin-(42-77), can bind. To address the physiological significance of the existence of dual ligands for a single receptor, we first compared the ability of the apelin fragments to regulate intracellular effectors, to promote G protein coupling, and to desensitize the response in Chinese hamster ovary cells expressing the murine apelin receptor. We found that both apelin fragments inhibited adenylyl cyclase and increased the phosphorylation of ERK or Akt. Using stably transfected cells expressing a pertussis toxin-insensitive ␣ i subunit, we demonstrated that each apelin fragment promoted coupling of the apelin receptor to either G␣ i1 or G␣ i2 but not to G␣ i3 . Although preincubation with each apelin fragment induced a desensitization at the level of the three effectors, preincubation with apelin-(42-77) also increased basal effector activity. In addition, a C-terminal deletion of the apelin receptor decreased the desensitization induced by apelin-(65-77) but did not alter the desensitization pattern induced by apelin-(42-77). Finally, in umbilical endothelial cells, which we have recently shown to express the apelin receptor, the G␣ i1 and G␣ i2 subunits are also expressed, ERK and Akt phosphorylation is desensitized after preincubation with apelin-(65-77), and basal levels of Akt phosphorylation are increased after preincubation with apelin-(42-77). In summary, apelin fragments regulate the same effectors, via the preferential coupling of the apelin receptor to G i1 or G i2 , but they promote a differential desensitization pattern that may be central to their respective physiological roles.The recently discovered apelin signaling pathway plays a role in the central and peripheral regulation of the cardiovascular system, in water and food intake, and possibly in immune function (for a review, see Ref.1). The apelin receptor was first identified in human (2) and amphibians (3), and the murine receptor was later cloned from embryonic tissues (4). The deduced protein sequence of these three orthologs revealed that the apelin receptor is a member of the G protein-coupled, seventransmembrane domain receptor family and displays a structural relationship with angiotensin receptors (2) and CXC chemokine receptors (3, 5). However, angiotensin II did not bind to it, and the receptor remained orphan until the identification of apelin, its endogenous ligand (6). Cloning of the apelin gene showed that it codes for a preproprotein of 77 residues containing a signal peptide, which, after proteolytic maturation, generates the apelin fragment of 36 amino acids, apelin-(42-77), first isolated from stomach extracts (6). Although the existence of several endogenous apelin fragments was inferred from the presence of conserved basic doublets in the protein sequence, their physiological occurrence has been validated by the characterization of two active peaks from stomach extracts (6) and by gel filtration chromatography of colostr...

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Section: Regulation Of Intracellular Effectors By Apelin Fragments Anmentioning

confidence: 98%

The Apelin Receptor Is Coupled to Gi1 or Gi2 Protein and Is Differentially Desensitized by Apelin Fragments

Masri¹,

Morin

Pedebernade

et al. 2006

Journal of Biological Chemistry

141

113

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“…Apelin was first isolated from stomach extracts, and studies on the actions of apelin in the gastrointestinal system have found functional, and possible cell survival, roles (Wang et al 2004, Susaki et al 2005, Han et al 2007). In the gastrointestinal system, apelin/APJ may be regulators of hormone (Wang et al 2004) and gastric acid (Ohno et al 2012) secretion.…”

Section: Other Functions Of the Apelinergic Systemmentioning

confidence: 99%

“…In the gastrointestinal system, apelin/APJ may be regulators of hormone (Wang et al 2004) and gastric acid (Ohno et al 2012) secretion. Apelin/APJ may also have a direct effect on vascular smooth muscle, including vasoconstriction, which may affect renal glomerular hemodynamic function in the rat kidney (Hus-Citharel et al 2008).…”

Section: Other Functions Of the Apelinergic Systemmentioning

confidence: 99%

The apelin receptor APJ: journey from an orphan to a multifaceted regulator of homeostasis

O’Carroll

Lolait

Harris

et al. 2013

Journal of Endocrinology

292

216

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The apelin receptor (APJ; gene symbol APLNR) is a member of the G protein-coupled receptor gene family. Neural gene expression patterns of APJ, and its cognate ligand apelin, in the brain implicate the apelinergic system in the regulation of a number of physiological processes. APJ and apelin are highly expressed in the hypothalamo-neurohypophysial system, which regulates fluid homeostasis, in the hypothalamic-pituitary-adrenal axis, which controls the neuroendocrine response to stress, and in the forebrain and lower brainstem regions, which are involved in cardiovascular function. Recently, apelin, synthesised and secreted by adipocytes, has been described as a beneficial adipokine related to obesity, and there is growing awareness of a potential role for apelin and APJ in glucose and energy metabolism. In this review we provide a comprehensive overview of the structure, expression pattern and regulation of apelin and its receptor, as well as the main second messengers and signalling proteins activated by apelin. We also highlight the physiological and pathological roles that support this system as a novel therapeutic target for pharmacological intervention in treating conditions related to altered water balance, stress-induced disorders such as anxiety and depression, and cardiovascular and metabolic disorders.

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“…Finally, adipocyte derived adipokines, such as adiponectin and leptin, also affect islet function (20,21). Although the function of apelin-36 still remains to be established, the peptide is of interest in this respect due to its localization to the stomach (8,10), adipocytes (12) and the hypothalamus (14). Its proposed action to be involved in the regulation of food intake (17) is also of interest in this context, because many bioactive peptides have the dual action to regulate food intake and islet function.…”

Section: Intravenous Glucosementioning

confidence: 99%

“…The endogenous ligand for the apj receptor is apelin, which was initially demonstrated in stomach extracts in 1998 (8). Later studies have shown that apelin mRNA is expressed in several tissues, as for example in several regions in the CNS, in the heart, lung, placenta, mammary gland and gastrointestinal tract (3,5,(9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

The apj receptor is expressed in pancreatic islets and its ligand, apelin, inhibits insulin secretion in mice

Winzell

Magnusson

Åhrén

2005

Regulatory Peptides

177

114

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Apelin is the endogenous ligand of the G-protein coupled apj receptor. Apelin is expressed in the brain, the hypothalamus and the stomach and was recently shown also to be an adipokine secreted from the adipocytes. Although apelin has been suggested to be involved in the regulation of food intake, it is not known whether the peptide affects islet function and glucose homeostasis. We show here that the apj receptor is expressed in pancreatic islets and that intravenous administration of full-length apelin-36 (2 nmol/kg) inhibits the rapid insulin response to intravenous glucose (1g/kg) by 35% in C57BL/6J mice. Thus, the acute (1-5 min) insulin response to intravenous glucose was 682±23 pmol/l after glucose alone (n=17) and 445±58 pmol/l after glucose plus apelin-36 (n=18; P=0.017). This was associated with impaired glucose elimination (the 5-20 min glucose elimination was 2.9±0.1%/min after glucose alone versus 2.3±0.2%/min after glucose plus apelin-36, P=0.008). Apelin (2nmol/kg) also inhibited the insulin response to intravenous glucose in obese insulin resistant high-fat fed C57BL/6J mice (P=0.041). After 60 min incubation of isolated islets from normal mice, insulin secretion in the presence of 16.7 mmol/l glucose was inhibited by apelin-36 at 1 µmol/l, whereas apelin-36 did not significantly affect insulin secretion at 2.8 or 8.3 mmol/l glucose or after stimulation of insulin secretion by KCl. Islet glucose oxidation at 16.7 mmol/l was not affected by apelin-36. We conclude that the apj receptor is expressed in pancreatic islets and that apelin-36 inhibits glucose-stimulated insulin secretion both in vivo and in vitro.This may suggest that the islet beta-cells are targets for apelin-36.

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Apelin, a New Enteric Peptide: Localization in the Gastrointestinal Tract, Ontogeny, and Stimulation of Gastric Cell Proliferation and of Cholecystokinin Secretion

Cited by 166 publications

References 24 publications

The Apelin Receptor Is Coupled to Gi1 or Gi2 Protein and Is Differentially Desensitized by Apelin Fragments

The Apelin Receptor Is Coupled to Gi1 or Gi2 Protein and Is Differentially Desensitized by Apelin Fragments

The apelin receptor APJ: journey from an orphan to a multifaceted regulator of homeostasis

The apj receptor is expressed in pancreatic islets and its ligand, apelin, inhibits insulin secretion in mice

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