Apelin, a peptide first isolated from bovine stomach tissue extracts, is the endogenous ligand of the human G protein-coupled orphan APJ receptor. The ligand was named “Apelin” after APJ endogenous ligand.
In 1993, O’Dowd et al. identified the gene for G-protein coupled receptor, named APJ, which shows about 30 % homology to the angiotensin receptor (AT-1)1. Thus, APJ remained an “orphaned” receptor until 1998 when Tatemoto et al. discovered the peptide apelin. These authors found that peptide-enriched fractions of bovine stomach-extracts promoted extra-cellular acidification rates of cells expressing the APJ receptor. By monitoring this activity, they purified, sequenced a 36 amino acid peptide named apelin2.
Apelin is a 36-aa peptide derived from a 77-aa precursor, preproapelin, for which cDNAs have been cloned from humans and animals. In all species a sequence of 23 amino acids in the C-terminal region is conserved, and is critical for biological activity.77-aa preproapelin contains a number of basic amino acid pairs (Arg – Arg, Arg – Lys) are the proteolytic cleavage site for endopeptidase. The endogenous forms detected (by chromatographic separation and immunoassay) comprise predominantly Apelin – 36, – 17, – 13 and following post translation modification by enzymatic conversion of N - terminal glutamate by pyroglutamate [Pyr1 ]. This modification confers resistance to degradation by peptidase2.
Mechanism of action
The transduction pathways for apelin signal depends on the interaction with a G-protein coupled to the APJ receptor, independently of Ras protein; although dependent on Protein Kinase C (PKC). If PKC, phospholipase C, the Na+-H+ and Na+-Ca2+ exchanger are inhibited, apelin effects significantly reduces (positive inotropic effect).
In addition to adenyl cyclase inhibition pathway, apelin activates ERKs (extracellular regulated kinases) pathways through a PTX (pertussis toxin) sensitive G-protein, in a PKC-dependent process. Endothelial cells proliferation control is also activated by apelin through two mechanisms: one is ERK-dependent and the other is PI3K-dependent. PI3K/Akt seems to be responsible for the phosphorilation and resulting activation of endothelial nitric oxide synthase, which is indispensable for apelin vasoactive effects3.
Apelin, the novel endogenous ligand of the orphan receptor APJ, regulates cardiac contractility- apelin exhibit high levels of mRNA expression in the heart. In isolated perfused rat hearts, infusion of apelin induced a dose-dependent positive inotropic effect. Inhibition of phospholipase C with U-73122 and suppression of protein kinase C with stauzrosporine and markedly attenuated the apelin-induced inotropic effect4.
The novel peptide apelin lowers blood pressure via a nitric oxide-dependent mechanism - mean arterial pressure after the administration of apelin-13, and apelin-36 in doses of 10 nmol/kg in anaesthetized rats was reduced by 11+/-4, and 5+/-4 mm Hg, respectively2.
Apelin-immunoreactivity in the rat hypothalamus and pituitary- Apelin-immunoreactive (IR) neurons are particularly abundant in hypothalamic nuclei, i.e., the supraoptic (SON), paraventricular (PVN) nuclei. It suggests that apelin-containing cell bodies of the SON and PVN, like arginine vasopressin (AVP) - and oxytocin (OXY)-containing magnocellular neurons, project toward the neural lobe of the pituitary. These two neurohormones released from posterior-pituitary into systemic circulation, control fluid balance and milk ejection/uterus contractility. Also it has been reported that apelin IR colocalizes with neurophysin-I in a population of SON and PVN magnocellular neurons, indicating that apelin is expressed by OXY neurons5.
The effects of centrally administered apelin-13 on rats - Preproapelin and APJ mRNA are found in hypothalamic regions known to be important in the regulation of food and water intake, and pituitary hormone release. The intracerebroventricular administration of pyroglutamylated apelin-13 on rats had little effect on food intake, but dose-dependently increased drinking behaviour and water intake. Apelin-13 increased water intake and also significantly increased plasma ACTH and corticosterone and decreased plasma prolactin, LH and FSH (endocrine axes), compared to saline control6.
1.O’Dowd, Heiber, Chan A, Heng, Tsui, Kennedy JL, Petronis A (1993). A human gene that shows identity with the gene encoding the angiotensin receptor is located on chromosome 11. Gene.,136:355–360.
2.Tatemoto K, Hosoya, Habata, Fujii R, Kakegawa T, Kawamata Y, Hinuma S, Kitada, Kurokawa T, Onda (1998). Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor. Biochem. Biophys. Res. Commun., 251:471–476
3.Ricardo Ladeiras-Lopes, João Ferreira-Martins, Adelino F. Leite-Moreira (2008). Apelinergic System: The Role Played in Human Physiology and Pathology and Potential Therapeutic Applications. Arq. Bras. Cardiol., 90(5): 343-349.
4.Szokodi I, Tavi, Foldes G, Voutilainen-Myllyla S, Tokola H (2002). Apelin, the novel endogenous ligand of the orphan receptor APJ, regulates cardiac contractility. Circ Res., 91 (5): 434-40.
5.Brailoiu C, Dun SL, Yang J, Ohsawa M, & Dun NJ (2002). Apelin-immunoreactivity in the rat hypothalamus and pituitary. Neurosci. Lett. 327 , 193–197.
6.Taheri S, Murphy K, Cohen M, Sujkovic E, Kennedy A, Dhillo W, Dakin C, Sajedi A, Ghatei M, Bloom S (2002). The effects of centrally administered apelin-13 on food intake, water intake and pituitary hormone release in rats. Biochem. Biophys. Res. Commun., 291: 1208–1212.