Alternative titles; symbols
HGNC Approved Gene Symbol: APLNR
Cytogenetic location: 11q12.1 Genomic coordinates (GRCh38): 11:57,233,591-57,237,250 (from NCBI)
In the course of a search for genes closely related to the vasopressin receptor gene (AVPR2; 300538), O'Dowd et al. (1993) found a putative receptor protein related to the angiotensin receptor (AGTR1A; 106165). The AGTRL1 gene, which they designated APJ, was cloned using PCR with a set of degenerate primers based on a conserved 7-transmembrane domain found in members of the G protein-coupled receptor (GPCR) gene family. The identity to the AGTR1A gene ranged from 40 to 50% in the hydrophobic transmembrane region of APJ. Transcripts of the gene were detected in many regions of the brain.
Tatemoto et al. (1998) stated that apelin (300297) is an endogenous ligand for the APJ receptor.
Cayabyab et al. (2000) reported that in addition to the chemokine receptors CCR5 (601373) and CXCR4 (162643), primary HIV-1 isolates can also use APJ as a coreceptor. CAT reporter assays showed that synthetic apelin peptides inhibited HIV-1 entry into CD4 (186940)-APJ-expressing cells.
Using cDNA microarray analysis on paired samples of left ventricle obtained before and after placement of a left ventricular assist device in 11 patients, Chen et al. (2003) found that APJ was the most significantly upregulated gene. Using immunoassay and immunohistochemical techniques, they demonstrated that apelin is localized primarily in the endothelium of the coronary arteries and is found at a higher concentration in cardiac tissue after mechanical offloading. The authors also demonstrated increases in the plasma level of apelin in patients with left ventricular dysfunction. Chen et al. (2003) concluded that their findings imply an important apelin-APJ paracrine signaling pathway in the heart.
Scimia et al. (2012) reported that genetic loss of APJ, a G protein-coupled receptor, confers resistance to chronic pressure overload by markedly reducing myocardial hypertrophy and heart failure. In contrast, mice lacking apelin, the endogenous APJ ligand, remain sensitive, suggesting an apelin-independent function of APJ. Freshly isolated APJ-null cardiomyocytes exhibit an attenuated response to stretch, indicating that APJ is a mechanosensor. Activation of APJ by stretch increases cardiomyocyte cell size and induces molecular markers of hypertrophy. Whereas apelin stimulates APJ to activate G-alpha-i (see 139310) and elicits a protective response, stretch signals in an APJ-dependent, G protein-independent fashion to induce hypertrophy. Stretch-mediated hypertrophy is prevented by knockdown of beta-arrestins (e.g., 107940) or by pharmacologic doses of apelin acting through G-alpha-i. Scimia et al. (2012) concluded that, taken together, their data indicated that APJ is a bifunctional receptor for both mechanical stretch and the endogenous peptide apelin. By sensing the balance between these stimuli, APJ occupies a pivotal point linking sustained overload to cardiomyocyte hypertrophy.
Chng et al. (2013) identified Elabela (ELA, or APELA; 615594), an evolutionarily conserved secreted peptide hormone. They found that Ela was expressed in zebrafish embryonic ectodermal cells. Knockout of Ela caused zebrafish embryos to develop with a rudimentary heart or no heart at all, which phenocopied the loss of Aplnr. Overexpression of zebrafish or human APLNR in HEK293 cells was sufficient to confer cell surface binding of zebrafish Ela conjugated to alkaline phosphatase (see 171760), indicating that APLNR is the cognate receptor for ELA.
Pauli et al. (2014) studied the relationship between Toddler (also known as Apela, Elabela, or Ende) and APJ/apelin receptors through genetic interaction and receptor internalization experiments. Loss or overproduction of Toddler reduced cell movements during zebrafish gastrulation; mesodermal and endodermal cells were slow to internalize and migrate. Both the local and ubiquitous expression of Toddler were able to rescue gastrulation movements in Toddler mutants, suggesting that Toddler acts as a motogen, a signal that promotes cell migration. Toddler activates G protein-coupled APJ/apelin receptor signaling, as evidenced by Toddler-induced internalization of APJ/apelin receptors and rescue of Toddler mutants through expression of the known receptor agonist apelin. Pauli et al. (2014) concluded that their findings indicated that Toddler promotes cell movement during zebrafish gastrulation by activation of APJ/apelin receptor signaling and that Toddler does not seem to act as a chemoattractant or -repellent, but rather as a global, signal that promotes the movement of mesendodermal cells. Since both loss and overproduction of Toddler reduce cell movement, Toddler levels need to be tightly regulated during gastrulation.
By PCR analysis of somatic cell lines, O'Dowd et al. (1993) mapped the APJ gene to chromosome 11. High-resolution mapping by fluorescence in situ hybridization sublocalized the gene to 11q12.
Cayabyab, M., Hinuma, S., Farzan, M., Choe, H., Fukusumi, S., Kitada, C., Nishizawa, N., Hosoya, M., Nishimura, O., Messele, T., Pollakis, G., Goudsmit, J., Fujino, M., Sodroski, J. Apelin, the natural ligand of the orphan seven-transmembrane receptor APJ, inhibits human immunodeficiency virus type 1 entry. J. Virol. 74: 11972-11976, 2000. [PubMed: 11090199] [Full Text: https://doi.org/10.1128/jvi.74.24.11972-11976.2000]
Chen, M. M., Ashley, E. A., Deng, D. X. F., Tsalenko, A., Deng, A., Tabibiazar, R., Ben-Dor, A., Fenster, B., Yang, E., King, J. Y., Fowler, M., Robbins, R., Johnson, F. L., Bruhn, L., McDonagh, T., Dargie, H., Yakhini, Z., Tsao, P. S., Quertermous, T. Novel role for the potent endogenous inotrope apelin in human cardiac dysfunction. Circulation 108: 1432-1439, 2003. [PubMed: 12963638] [Full Text: https://doi.org/10.1161/01.CIR.0000091235.94914.75]
Chng, S. C., Ho, L., Tian, J., Reversade, B. ELABELA: a hormone essential for heart development signals via the apelin receptor. Dev. Cell 27: 672-680, 2013. [PubMed: 24316148] [Full Text: https://doi.org/10.1016/j.devcel.2013.11.002]
O'Dowd, B. F., Heiber, M., Chan, A., Heng, H. H. Q., Tsui, L.-C., Kennedy, J. L., Shi, X., Petronis, A., George, S. R., Nguyen, T. A human gene that shows identity with the gene encoding the angiotensin receptor is located on chromosome 11. Gene 136: 355-360, 1993. [PubMed: 8294032] [Full Text: https://doi.org/10.1016/0378-1119(93)90495-o]
Pauli, A., Norris, M. L., Valen, E., Chew, G.-L., Gagnon, J. A., Zimmerman, S., Mitchell, A., Ma, J., Dubrulle, J., Reyon, D., Tsai, S. Q., Joung, J. K., Saghatelian, A., Schier, A. F. Toddler: an embryonic signal that promotes cell movement via apelin receptors. Science 343: 1248636, 2014. Note: Electronic Article. [PubMed: 24407481] [Full Text: https://doi.org/10.1126/science.1248636]
Scimia, M. C., Hurtado, C., Ray, S., Metzler, S., Wei, K., Wang, J., Woods, C. E., Purcell, N. H., Catalucci, D., Akasaka, T., Bueno, O. F., Vlasuk, G. P., Kaliman, P., Bodmer, R., Smith, L. H., Ashley, E., Mercola, M., Brown, J. H., Ruiz-Lozano, P. APJ acts as a dual receptor in cardiac hypertrophy. Nature 488: 394-398, 2012. [PubMed: 22810587] [Full Text: https://doi.org/10.1038/nature11263]
Tatemoto, K., Hosoya, M., Habata, Y., Fujii, R., Kakegawa, T., Zou, M.-X., Kawamata, Y., Fukusumi, S., Hinuma, S., Kitada, C., Kurokawa, T., Onda, H., Fujino, M. Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor. Biochem. Biophys. Res. Commun. 251: 471-476, 1998. [PubMed: 9792798] [Full Text: https://doi.org/10.1006/bbrc.1998.9489]