Summary
Because G-protein-coupled receptors (GPCRs) constitute excellent putative therapeutic targets, functional characterization of orphan GPCRs through identification of their endogenous ligands has great potential for drug discovery. In an attempt to identify a receptor specific for angiotensin III, we have cloned, by homology from a rat brain cDNA library, a GPCR that shares 90% amino acid sequence identity with the human orphan APJ (putative receptor protein related to the angiotensin receptor AT1) receptor and 31% with the rat AT1A angiotensin receptor. In 1998, the endogenous ligand for the human orphan APJ receptor, i.e., apelin, was isolated from bovine stomach extracts. Apelin, a bioactive peptide, naturally occurs in the brain and plasma as 13 (pE13F) and 17 amino acid (K17F) fragments of a 77 amino acid precursor. The APJ receptor binds with high affinity K17F and pE13F but not the shorter N-terminal-deleted apelin fragments. This receptor is negatively coupled to adenylate cyclase and internalizes following stimulation with K17F and pE13F. Apelin and its receptor are both widely distributed in the brain and are highly expressed in the supraoptic and paraventricular hypothalamic nuclei. Dual labeling studies demonstrate that, within these two types of nuclei, apelin and its receptor co-localize with vasopressin (AVP) in magnocellular neurons. In lactating rodents, characterized by increases in synthesis and release of AVP, central injection of apelin inhibits the phasic electrical activity of AVP neurons and reduces the secretion of AVP in the bloodstream, resulting in aqueous diuresis. Apelin may thus be considered as a natural inhibitor of the anti-diuretic effect of AVP. Moreover, water deprivation, which increases systemic AVP release, decreases plasma apelin concentrations and induces apelin storage inside magnocellular neurons, thereby avoiding the inhibitory action of apelin on AVP release. Thus apelin and AVP are conversely regulated to optimize systemic AVP release and prevent additional water loss at the kidney level.
In addition, apelin and its receptor are present in the cardiovascular system, i.e., in heart, kidney and vessels. Given systemically, apelin reduces arterial blood pressure, increases cardiac contractility and reduces cardiac loading. Apelin may therefore play a crucial role in the control of body fluid homeostasis and cardiovascular functions. A clinical study in healthy volunteers to determine whether apelin controls water balance in humans is in progress. If this hypothesis is confirmed, the development of non-peptide agonists of the apelin receptor may therefore represents new therapeutic avenues for the treatment of water/sodium retention, heart and kidney failure.
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References
Allen AM, Paxinos G, Song KF, Mendelsohn FAO (1992) Localization of angiotensin receptor binding sites in the rat brain. In: Björklund A, Hökfelt T, Kuhar MJ (eds) Handbook of chemical neuroanatomy: Neuropeptide receptors in the CNS. Elsevier, Amsterdam, p 1–37
Ashley EA, Powers J, Chen M, Kundu R, Finsterbach T, Caffarelli A, Deng A, Eichhorn J, Mahajan R, Agrawal R, Greve J, Robbins R, Patterson AJ, Bernstein D, Quertermous T (2005) The endogenous peptide apelin potently improves cardiac contractility and reduces cardiac loading in vivo. Cardiovasc Res 65:73–82
Berry MF, Pirolli TJ, Jayasankar V, Burdick J, Morine KJ, Gardner TJ, Woo YJ (2004) Apelin has in vivo inotropic effects on normal and failing hearts. Circulation 110:87–93
Brailoiu GC, Dun SL, Yang J, Ohsawa M, Chang JK, Dun NJ (2002) Apelin-immunoreactivity in the rat hypothalamus and pituitary. Neurosci Lett 327:193–197
Brownstein MJ, Russell JT, Gainer H (1980) Synthesis, transport, and release of posterior pituitary hormones. Science 207:373–378
Chartrel N, Dujardin C, Anouar Y, Leprince J, Decker A, Clerens S, Do-Rego JC, Vandesande F, Llorens-Cortes C, Costentin J, Beauvillain JC, Vaudry H (2003) Identification of 26RFa, a hypothalamic neuropeptide of the RFamide peptide family with orexigenic activity. Proc Natl Acad Sci USA 100:15247–15252
Chauvel EN, Coric P, Llorens-Cortes C, Wilk S, Roques BP, Fournie-Zaluski MC (1994) Investigation of the active site of aminopeptidase A using a series of new thiol-containing inhibitors. J Med Chem 37:1339–1346
Chen MM, Ashley EA, Deng DX, Tsalenko A, Deng A, Tabibiazar R, Ben-Dor A, Fenster B, Yang E, King JY, Fowler M, Robbins R, Johnson FL, Bruhn L, McDonagh T, Dargie H, Yakhini Z, Tsao PS, Quertermous T (2003) Novel role for the potent endogenous inotrope apelin in human cardiac dysfunction. Circulation 108:1432–1439
Conklin BR, Herzmark P, Ishida S, Voyno-Yasenetskaya TA, Sun Y, Farfel Z, Bourne HR (1996) Carboxyl-terminal mutations of Gq alpha and Gs alpha that alter the fidelity of receptor activation. Mol Pharmacol 50:885–890
De Mota N, Lenkei Z, Llorens-Cortes C (2000) Cloning, pharmacological characterization and brain distribution of the rat apelin receptor. Neuroendocrinology 72:400–407
De Mota N, Reaux-Le Goazigo A, El Messari S, Chartrel N, Roesch D, Dujardin C, Kordon C, Vaudry H, Moos F, Llorens-Cortes C (2004) Apelin, a potent diuretic neuropeptide counteracting vasopressin actions through inhibition of vasopressin neuron activity and vasopressin release. Proc Natl Acad Sci USA 101:10464–10469
Devic E, Rizzoti K, Bodin S, Knibiehler B, Audigier Y (1999) Amino acid sequence and embryonic expression of msr/apj, the mouse homolog of Xenopus X-msr and human APJ. Mech Dev 84:199–203
El Messari S, Iturrioz X, Fassot C, De Mota N, Roesch D, Llorens-Cortes C (2004) Functional dissociation of apelin receptor signaling and endocytosis: implications for the effects of apelin on arterial blood pressure. J Neurochem 90:1290–1301
Foldes G, Horkay F, Szokodi I, Vuolteenaho O, Ilves M, Lindstedt KA, Mayranpaa M, Sarman B, Seres L, Skoumal R, Lako-Futo Z, deChatel R, Ruskoaho H, Toth M (2003) Circulating and cardiac levels of apelin, the novel ligand of the orphan receptor APJ, in patients with heart failure. Biochem Biophys Res Commun 308:480–485
Gouzenes L, Desarmenien MG, Hussy N, Richard P, Moos FC (1998) Vasopressin regularizes the phasic firing pattern of rat hypothalamic magnocellular vasopressin neurons. J Neurosci 18:1879–1885
Habata Y, Fujii R, Hosoya M, Fukusumi S, Kawamata Y, Hinuma S, Kitada C, Nishizawa N, Murosaki S, Kurokawa T, Onda H, Tatemoto K, Fujino M (1999) Apelin, the natural ligand of the orphan receptor APJ, is abundantly secreted in the colostrum. Biochim Biophys Acta 13:25–35
Hosoya M, Kawamata Y, Fukusumi S, Fujii R, Habata Y, Hinuma S, Kitada C, Honda S, Kurokawa T, Onda H, Nishimura O, Fujino M (2000) Molecular and functional characteristics of APJ. Tissue distribution of mRNA and interaction with the endogenous ligand apelin. J Biol Chem 275:21061–21067
Hurbin A, Boissin-Agasse L, Orcel H, Rabie A, Joux N, Desarmenien MG, Richard P, Moos FC (1998) The V1a and V1b, but not V2, vasopressin receptor genes are expressed in the supraoptic nucleus of the rat hypothalamus, and the transcripts are essentially colocalized in the vasopressinergic magnocellular neurons. Endocrinology 139:4701–4707
Ishida J, Hashimoto T, Hashimoto Y, Nishiwaki S, Iguchi T, Harada S, Sugaya T, Matsuzaki H, Yamamoto R, Shiota N, Okunishi H, Kihara M, Umemura S, Sugiyama F, Yagami K, Kasuya Y, Mochizuki N, Fukamizu A (2004) Regulatory roles for APJ, a seven-transmembrane receptor related to angiotensin-type 1 receptor in blood pressure in vivo. J Biol Chem 279:26274–26279
Katugampola S, Davenport A (2003) Emerging roles for orphan G-protein-coupled receptors in the cardiovascular system. Trends Pharmacol Sci 24:30–35
Kawamata Y, Habata Y, Fukusumi S, Hosoya M, Fujii R, Hinuma S, Nishizawa N, Kitada C, Onda H, Nishimura O, Fujino M (2001) Molecular properties of apelin: tissue distribution and receptor binding. Biochim Biophys Acta 23:2–3
Kleinz MJ, Davenport AP (2004) Immunocytochemical localization of the endogenous vasoactive peptide apelin to human vascular and endocardial endothelial cells. Regul Pept 118:119–125
Lee DK, Cheng R, Nguyen T, Fan T, Kariyawasam AP, Liu Y, Osmond DH, George SR, O’Dowd BF (2000) Characterization of apelin, the ligand for the APJ receptor. J Neurochem 74:34–41
Lenkei Z, Palkovits M, Corvol P, Llorens-Cortes C (1997) Expression of angiotensin type-1 (AT1) and type-2 (AT2) receptor mRNAs in the adult rat brain: a functional neuroanatomical review. Front Neuroendocrinol 18:383–439
Lenkei Z, Beaudet A, Chartrel N, De Mota N, Irinopoulou T, Braun B, Vaudry H, Llorens-Cortes C (2000) A highly sensitive quantitative cytosensor technique for the identification of receptor ligands in tissue extracts. J Histochem Cytochem 48:1553–1564
Llorens Cortes C, Beaudet A (2005) Apelin, a new peptide that conteracts vasopressin secretion. Med Sci (Paris) 21:741–746
Ludwig M (1998) Dendritic release of vasopressin and oxytocin. J Neuroendocrinol 10:881–895
Manning M, Lowbridge J, Haldar J, Sawyer WH (1997) Design of neurohypophyseal peptides that exhibit selective agonistic and antagonistic properties. Fed Proc 36:1848–1852
McConnell HM, Owicki JC, Parce JW, Miller DL, Baxter GT, Wada HG, Pitchford S (1992) The cytosensor microphysiometer: biological applications of silicon technology. Science 257:1906–1912
Murphy TJ, Alexander RW, Griendling KK, Runge MS, Bernstein KE (1991) Isolation of a cDNA encoding the vascular type-1 angiotensin II receptor. Nature 351:233–236
O’Carroll AM, Selby TL, Palkovits M, Lolait SJ (2000) Distribution of mRNA encoding B78/apj, the rat homologue of the human APJ receptor, and its endogenous ligand apelin in brain and peripheral tissues. Biochim Biophys Acta 21:72–80
O’Carroll AM, Don AL, Lolait SJ (2003) APJ receptor mRNA expression in the rat hypothalamic paraventricular nucleus: regulation by stress and glucocorticoids. J Neuroendocrinol 15:1095–1101
O’Dowd BF, Heiber M, Chan A, Heng HH, Tsui LC, Kennedy JL, Shi X, Petronis A, George SR, Nguyen T (1993) A human gene that shows identity with the gene encoding the angiotensin receptor is located on chromosome 11. Gene 136:355–360
Offermanns S, Simon MI (1995) G alpha 15 and G alpha 16 couple a wide variety of receptors to phospholipase C. J Biol Chem 270:15175–15180
Reaux A, Fournie-Zaluski MC, David C, Zini S, Roques BP, Corvol P, Llorens-Cortes C (1999) Aminopeptidase A inhibitors as potential central antihypertensive agents. Proc Natl Acad Sci USA 96:13415–13420
Reaux A, De Mota N, Skultetyova I, Lenkei Z, El Messari S, Gallatz K, Corvol P, Palkovits M, Llorens-Cortes C (2001) Physiological role of a novel neuropeptide, apelin, and its receptor in the rat brain. J Neurochem 77:1085–1096
Reaux A, Gallatz K, Palkovits M, Llorens-Cortes C (2002) Distribution of apelin-synthesizing neurons in the adult rat brain. Neuroscience 113:653–662
Reaux-Le Goazigo AR, Morinville A, Burlet A, Llorens-Cortes C, Beaudet A (2004) Dehydration-induced cross-regulationof apelin and vasopressin immunoreactivity levels in magnocellular hypothalamic neurons. Endocrinology 145:4392–4400
Stadel JM, Wilson S, Bergsma DJ (1997) Orphan G protein-coupled receptors: a neglected opportunity for pioneer drug discovery. Trends Pharmacol Sci 18:430–437
Tatemoto K, Hosoya M, Habata Y, Fujii R, Kakegawa T, Zou MX, Kawamata Y, Fukusumi S, Hinuma S, Kitada C, Kurokawa T, Onda H, Fujino M (1998) Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor. Biochem Biophys Res Commun 251:471–476
Tatemoto K, Takayama K, Zou MX, Kumaki I, Zhang W, Kumano K, Fujimiya M (2001) The novel peptide apelin lowers blood pressure via a nitric oxide-dependent mechanism. Regul Pept 99:87–92
Vassilatis DK, Hohmann JG, Zeng H, Li F, Ranchalis JE, Mortrud MT, Brown A, Rodriguez SS, Weller JR, Wright AC, Bergmann JE, Gaitanaris GA (2003) The G protein-coupled receptor repertoires of human and mouse. Proc Natl Acad Sci USA 100:4903–4908
Wise A, Gearing K, Rees S (2002) Target validation of G-protein coupled receptors. Drug Discov Today 7:235–246
Zhang JV, Ren PG, Avsian-Kretchmer O, Luo CW, Rauch R, Klein C, Hsueh AJ (2005) Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin’s effects on food intake. Science 310:996–999
Zingg HH, Lefebvre D, Almazan G (1986) Regulation of vasopressin gene expression in rat hypothalamic neurons. Response to osmotic stimulation. J Biol Chem 261:12956–12959
Zini S, Fournie-Zaluski MC, Chauvel E, Roques BP, Corvol P, Llorens-Cortes C (1996) Identification of metabolic pathways of brain angiotensin II and III using specific aminopeptidase inhibitors: predominant role of angiotensin III in the control of vasopressin release. Proc Natl Acad Sci USA 93:11968–11973
Zini S, Demassey Y, Fournie-Zaluski MC, Bischoff L, Corvol P, Llorens-Cortes C, Sanderson P (1998) Inhibition of vasopressinergic neurons by central injection of a specific aminopeptidase A inhibitor. Neuroreport 9:825–828
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Iturrioz, X. et al. (2006). Central Neuropeptide Receptors Involved in Water Balance: Application to Apelin. In: Conn, M., Kordon, C., Christen, Y. (eds) Insights into Receptor Function and New Drug Development Targets. Research and Perspectives in Endocrine Interactions. Springer, Berlin, Heidelberg . https://doi.org/10.1007/3-540-34447-0_5
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