Abstract
The apelin receptor (APJ) is a member of the family A of G-protein-coupled receptors (GPCRs) and is involved in range of physiological and pathological functions, including fluid homeostasis, anxiety, and depression, as well as cardiovascular and metabolic disorders. APJ was classically described as a monomeric transmembrane receptor that forms a ternary complex together with its ligand and associated G proteins. More recently, increasing evidence indicates that APJ may interact with other GPCRs to form heterodimers, which may selectively modulate distinct intracellular signal transduction pathways. Besides, the apelin/APJ system plays important roles in the physiology and pathophysiology of several organs, including regulation of blood pressure, cardiac contractility, angiogenesis, metabolic balance, and cell proliferation, apoptosis, or inflammation. Additionally, the apelin/APJ system is widely expressed in the central nervous system, especially in neurons and oligodendrocytes. This article reviews the role of apelin/APJ in energy metabolism and water homeostasis. Compared with the traditional diuretics, apelin exerts a positive inotropic effect on the heart, while increases water excretion. Therefore, drugs targeting apelin/APJ system undoubtedly provide more therapeutic options for patients with congestive heart failure accompanied with hyponatremia. To provide more precise guidance for the development of clinical drugs, further in-depth studies are warranted on the metabolism and signaling pathways associated with apelin/APJ system.
Highlights
The apelin receptor (APJ) was first identified as an orphan G protein-coupled receptor (GPCR) in 1993, with the closest identity to the angiotensin II (Ang II) receptor, type AT1a (O’Dowd et al, 1993)
The effects of apelin on glucose metabolism in the gut-brain axis were experimentally investigated by Fournel et al (2017) in normal and obese/diabetic mice, glucose utilization is improved by the decrease of enteric nervous system (ENS)-evoked duodenal contraction activities in response to apelin, causing an increase in hypothalamic release of nitric oxide (NO)
In the hypothalamic explant experiment, NO release content and endothelial nitric oxide synthase (eNOS) phosphorylation form of obese diabetic mice did not change in either normal feeding or fasting state, in presence of low- or high-dose ICV injection (Duparc et al, 2011a). These results suggest that central apelin-dependent NO signaling pathway is impaired in pathological conditions, e.g., obesity or diabetes, or there are other pathways regulating glucose metabolism in the central nervous system (CNS)
Summary
The apelin receptor (APJ) was first identified as an orphan G protein-coupled receptor (GPCR) in 1993, with the closest identity to the angiotensin II (Ang II) receptor, type AT1a (O’Dowd et al, 1993). APJ belongs to family A of the GPCRs (O’Dowd et al, 1993), and is a potential pharmacotherapeutic target for heart failure, hypertension, and other cardiovascular diseases. APJ shares 31% identity with the amino acid sequence of the human AT1 receptor, and its hydrophobic transmembrane region shares 54% identity with human AT1 (O’Dowd et al, 1993), while it does not bind to members of the angiotensin family (De Mota et al, 2000). APJ remained an orphan receptor until 1998 when Tatemoto et al (Tatemoto et al, 1998; Lee et al, 2000) identified a 36-amino acid peptide termed Apelin, for APJ endogenous ligand
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