Apelin receptor: Introduction

Apelin Receptor

In 1993, a gene encoding a novel class A G-protein-coupled receptor was discovered by homology cloning. It showed greatest sequence homology with the angiotensin AT1 receptor (54% in the transmembrane regions) but did not bind angiotensin II. It was therefore designated an "orphan" GPCR, having no known ligand, and was named APJ by O'Dowd et al., (1993) [51]. The approved Human Genome Organization (HUGO) gene symbol for APJ is now APLNR. The endogenous ligand for this receptor was later identified as apelin, which led the International Union of Pharmacology (IUPHAR) to recommend “apelin receptor” as the nomenclature for the receptor protein [54]. This follows the convention of naming the receptor protein after its endogenous ligand.

The human apelin receptor comprises 380 amino acid residues and has the typical 7-transmembrane domain structure of a class A GPCR. It contains consensus sites for phosphorylation by cAMP-dependent protein kinase, palmitoylation, and glycosylation [51]. The apelin receptor has been identified in a number of other species, including mouse, rat, cow, rhesus macaque, Xenopus laevis, and Danio rerio.

To date, there is no evidence for multiple receptor subtypes in mammals. During the initial receptor identification, a polymerase chain reaction strategy using oligonucleotides based on the apelin receptor yielded no closely related genes [51]. In addition, saturation binding experiments in human tissues gave Hill coefficients close to unity, indicating that the radioligand bound to a single receptor population [30], although this does not exclude the possibility of two receptor subtypes with the same affinity.

Activation of apelin receptors expressed in cell lines inhibited forskolin-stimulated cAMP production, suggesting that the receptor is coupled to inhibitory G-proteins (Gi) [19], which is supported by the finding that apelin actions are pertussis toxin-sensitive [22,44]. A number of interactions between the apelin and angiotensin systems have been reported, including recent evidence that the apelin receptor forms heterodimers with the angiotensin AT1 receptor [9].

Apelin Peptides

In 1998, the endogenous ligand for APJ was identified as a 36-amino acid peptide named apelin (for APJ endogenous ligand), isolated from bovine stomach extracts. This peptide induced extracellular acidification in CHO cells expressing apelin receptors [65]. cDNA encoding a 77-amino acid prepropeptide (preproapelin) was identified in human and bovine tissue [65], showing considerable sequence similarity across all species examined, with the last 23 residues of the C terminus being identical in mammals. Apelin peptides so far have been detected in vascular and endocardial endothelial cells [34-35], in cells from the epithelial layer of the stomach mucosa [61], and in neurones of the supraoptic and paraventricular nuclei of the hypothalamus [55].

Preproapelin contains a number of paired basic amino acids residues (Arg-Arg and Arg-Lys) that are possible cleavage sites for endopeptidases [19]. Cleavage at these sites would produce a predicted family of C-terminal fragments, including apelin-36, apelin-17, apelin-13, and the post-translationally modified (Pyr1)apelin-13, which are all agonists at the apelin receptor. The degradative pathway for apelin peptides is unknown, but angiotensin-converting enzyme 2 (ACE2) cleaves the C-terminal phenylalanine from apelin-13 and apelin-36 [69]. All of these predicted isoforms have been shown to be present in vivo, but the predominant apelin isoform in human cardiac tissue is (Pyr1)apelin-13 [42], which is not unexpected because the pyroglutamate moiety protects the N terminus of peptides from exopeptidase degradation [68]. The predominant isoforms in plasma are (Pyr1)apelin-13, apelin-13 and apelin-17 [3,14,48]. The relative potency of the apelin peptides varies between experimental systems, (Pyr1)apelin-13 and apelin-13 being the most potent activators of apelin receptors expressed in cell lines [19,31,47,65], whereas apelin-36 is the most potent inhibitor of HIV infection of cells in vitro [72]. However, (Pyr1)apelin-13, apelin-13, and apelin-36 are equipotent mediators of vascular tone and cardiac contractility in human tissues in vitro [42].

A number of synthetic apelin analogs have biological activity. Three cyclic apelin analogues have been reported to show agonism at the apelin receptor, inhibiting cAMP accumulation in a pertussis toxin-sensitive manner, although binding data of these analogues are not available [20]. Another cyclic analogue, MM54, was designed and shown be the first specific antagonist at the apelin receptor showing high affinity at apelin receptor transfected in Chinese Hamster Ovary cells and at the native receptor in human left ventricle. MM54 displayed no agonist activity in cAMP accumulation assays, but shifted the (Pyr1)apelin-13 dose–response curve to the right in a dose-dependent manner, with no change in maximum response, typical of a competitive antagonist [41]. Furthermore, apelin-13 with the C-terminal phenylalanine mutated to alanine (Apelin-13(F13A)) has been hown to act as an apelin-specific functional antagonist in rats in vivo, blocking the hypotensive effects of apelin-13 [39]. However, three conflicting reports including two alanine scanning studies showed that apelin-13(F13A) had comparable affinity and agonist activity at the native apelin receptor in human cardiovascular tissues in vitro and at the human apelin receptor expressed in human embryonic kidney 293 cells [16,47,53], indicating that this peptide is a full agonist in man.

A non-peptide ligand of the apelin receptor, E339–3D6, was reported to behave as a partial agonist with regard to cAMP production and a full agonist with regard to apelin receptor internalization. This ligand induced vasorelaxation of precontracted rat aorta and potently inhibited systemic vasopressin release in water-deprived mice when intracerebroventricularly injected [25]. Additionally, ALX40-4C, a small-molecule antagonist of the chemokine receptor CXCR4, has been shown to directly bind apelin receptors expressed in cell lines and to block ligand-induced receptor internalization and signaling, suggesting it is a nonspecific apelin receptor antagonist [71]. A recent high throughput screen has identified ML221, a potent functional small molecule antagonist in cell-based assays that is highly selective for the apelin receptor against other related GPCRs [43]. The discoverers of ML221 have also reported ML233 from the screen as a potent and selective small molecule apelin receptor functional agonist in cell-based assays, and claimed it as the first non-peptide based agonist and E339–3D6 as a peptidomimetic [32].

A number of radiolabeled ligands for the apelin receptor have been synthesized based on the structure of the endogenous ligands, but most are based on (Pyr1)apelin-13. [125I](Pyr1)apelin-13 binds to receptors in human left ventricle with a KD of 0.35 nM. It associates rapidly, with a half-time for association of 6 min, and dissociates with a half-time for dissociation of 53 min [30]. It is noteworthy that analogues of this radioligand have been made by others with modifications at position 75 [22], replacing the methionine at this position with norleucine to prevent possible oxidation during the radiolabeling process, because oxidized (Pyr1)apelin-13 was found to be inactive. The resulting radioligand, [125I](Pyr1)[Nle75,Tyr77]apelin-13, is commercially available. Another group oxidized the methionine at this position, because the unoxidized form of the radioligand was very unstable [47].


Since the discovery of apelin as the endogenous ligand for APJ in 1998, a number of physiological roles for the receptor have emerged, including regulation of cardiovascular function, fluid homeostasis, the adipoinsular axis, gastrointestinal and immunomodulatory functions, reviewed by Pitkin et al., (2010) [53].

Apelin modulates vascular tone in vivo, causing a reduction in blood pressure when infused into rats [8,15,24,38-39,49,55,66] and vasodilation of resistance vessels when infused into the human forearm [26], both responses mediated primarily by nitric oxide. In vitro, apelin causes vasodilation of human splanchnic artery, largely via a nitric oxide-dependent mechanism [59]. Apelin also causes vasoconstriction of human saphenous vein [30] and mammary artery [42] in vitro by a direct action on vascular smooth muscle. These data support a role for the apelin system in modulation of vascular tone, where apelin released from endothelial cells would act on apelin receptors on the endothelium to cause vasodilation or on underlying smooth muscle cells to cause vasoconstriction. Apelin also modulates cardiac function. Apelin peptides have positive inotropic effects in rats [2,4,27] and mice [1] in vivo. In vitro studies have demonstrated that apelins are potent positive inotropic agents by a direct action on cardiac tissue in rat [12,17,62] and human [42]. It is noteworthy that apelins are the most potent endogenous inotropic agents yet reported in isolated cardiac tissue, with EC50 values of 40 to 125 pM in human tissue [42] and 33 pM in rat tissue [62]. In addition, apelin is a potent angiogenic factor [10,29] and mitogen of endothelial cells [29,45] and vascular smooth muscle cells [40]. Mice lacking the apelin gene show retardation of retinal vascular development [28] and narrow blood vessels in intersomitic vessels during embryogenesis [33], whereas APLNR(−/−) mice have cardiac developmental defects [7]. It has recently been shown that apelin acts downstream of Cripto (official gene name tdgf-1) to specify murine embryonic stem cells toward the cardiac lineage [11].

The colocalization of apelin and its receptor with vasopressin in magnocellular neurons of the SON and PVN of the hypothalamus triggered investigation of their role in fluid homeostasis. Apelin, given to mice by intracerebroventricular injection, inhibits vasopressin neuron activity and vasopressin release, decreasing plasma vasopressin concentration and increasing diuresis [14]. Dehydration increases apelin [56] and apelin receptor [50] expression and decreases vasopressin expression in rat magnocellular neurons [56]. In addition to its central effects, apelin has direct actions on the microvasculature of the kidney [23]. APLNR(−/−) mice have abnormal fluid homeostasis and altered responses to osmotic stress [57-58]. Osmotic stimuli have been show to exert opposing effects on plasma apelin and vasopressin in man; increased plasma osmolality increases plasma vasopressin and decreases plasma apelin, and vice versa [3].

Apelin is expressed and released by cultured adipocytes, identifying it as a novel adipokine [5], and adipose tissue is a possible source of plasma apelin. Apelin expression in adipose tissue is regulated by factors such as fasting and refeeding [5], insulin [5,70], hypoxia [18,37], growth hormone [36], tumor necrosis factor α [13], and peroxisome proliferator-activated receptor γ coactivator 1α [46]. Whereas insulin stimulates adipose apelin expression [5,70], apelin inhibits insulin secretion [63], presenting an interesting interaction between the two systems. There is evidence for a role for apelin regulation of adiposity, peripherally administered apelin causing no change in food intake [21,60] but decreasing adiposity, possibly by up-regulating uncoupling proteins and increasing energy expenditure [21]. However, investigation of the role of central apelin on food intake and body weight has yielded disparate results [52,60,64,67]. Apelin may also be involved in vascularization of adipose tissue [37].

APJ has further been reported to be a co-receptor for the infection of CD4-positive cells with subtypes of human immunodeficiency virus in the central nervous system. Another interesting action of apelin peptides is their ability to effectively inhibit HIV infection by blocking the HIV co-receptor APJ, with apelin-36 being the most potent anti-infective form of apelin [6,16,72].

Further information is available from the Pharmacological Review [53] by the International Union of Basic and Clinical Pharmacology. LXXIV. Apelin receptor nomenclature, distribution, pharmacology, and function.


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