The functional similarity between GPR and APLNR ie both

The functional similarity between GPR25 and APLNR, ie both can be activated by Apelin and Apela and are coupled to Gi-cAMP signaling pathway (Fig. 2, Fig. 3, Fig. 4), strongly suggests that GPR25 signaling may play important physiological and pathological roles in vertebrates more or less similar to those of APLNR signaling, such as regulation of blood pressure [4,11]. Despite the failure of Apelin and Apela in activating human GPR25 in vitro, the activation of GPR25 by Apelin or Apela in vivo should not be ruled out, as this may be possible in the presence of some unknown accessory CARIPORIDE receptor in vivo. In addition, there has been increasing evidence showing that many GPCRs possess constitutive activity in the absence of their endogenous ligands, such as melanocortin receptor 4 (MC4R) in the absence of α-melanocyte-stimulating hormone (α-MSH) [22]. Therefore, there is also a possibility that GPR25 may possess constitutive activity to regulate physiological/pathological processes, such as blood pressure and arterial stiffness in humans [4]. It is reported that APLNR is capable of forming hetero-dimers with other GPCRs, such as kappa opioid receptor [23], thus, we should not exclude the possibility that GPR25 may hetero-dimerize with other GPCR(s) (e.g. APLNR) to exert its functions. Our future studies on these issues will help to define the functionality of vertebrate GPR25 more precisely. To understand the physiological roles of GPR25 in vertebrates, RNA-Seq data was used to analyze the distribution of GPR25 in zebrafish, spotted gars and humans (Supplementary Fig. 6). GPR25 mRNA was detected to be widely expressed in most tissues examined, including the brain, heart, gills, kidneys, bones, intestines and testes of zebrafish and spotted gars. Although zebrafish APLNR was previously reported to be expressed in abundance during embryonic development [8,9], GPR25 mRNA was hardly detected in zebrafish embryos. It implies that unlike APLNR, GPR25 signaling may not play an active role in zebrafish embryogenesis [8]. Like zebrafish and spotted gar GPR25, human GPR25 mRNA is also expressed in a variety of tissues, including the testes and intestines [24]. The wide tissue distribution of GPR25 across vertebrate species hints that GPR25 may play a wide range of roles in vertebrates, which is worthy of further investigation.
Competing financial interests
Acknowledgments This work was supported by grants from the National Natural Science Foundation of China (31572391, 31472089, 31772590, 31771375) and the National Pilot Project for fostering top-notch students in Basic Sciences.
Introduction Coronary artery disease (CAD) along with other complications including hypertension and myocardial infarction (MI) account for a vast number of morbidity and mortality rates around the world [1]. In addition to environmental factors, genetic ones can affect the development and progression of CAD as 40% to 60% of the risk for CAD is reported to be due to the latter [2]. Of the genetic factors, single nucleotide polymorphisms (SNPs) assume great importance to the extent that previous studies have shown a multitude of SNPs which are associated with CAD and hypertension [3]. One of the most significant health challenges in the world capable of leading to other fatal diseases as well is hypertension which is regarded as one of the CAD risk factors [4]. It should be noted that nearly 12 million 25–64-year old Iranians are suffering from hypertension [5]. Apelin is an endogenous ligand for apelin receptor (APLNR) coupled with G protein that could be detected in plasma and expressed on the surface of cells such as heart, lung, kidney, adipose tissue, gastrointestinal tract, brain, adrenal glands and endothelium [6, 7]. Located in the X chromosome (Xq25–26.1) and containing 3 exons with a coding region ranging from exons 1 to 2, apelin gene encodes pro-protein 77 amino acids, which are later broken into smaller pieces and processed into a number of regulatory hormones [8]. APLNR expression and its activation contribute to controlling blood pressure and angiogenesis [9]. It is worth noting that the activation of APLNRs leads to secretion of nitric oxide (NO) which in turn brings about vascular wall smooth muscle cells [10]. Moreover, triggering intracellular signaling cascades by phosphorylation of extracellular signal–regulated kinases (ERKs), Akt and p70S6 kinases, apelin stimulates endothelial proliferation and angiogenesis [11].