Discovery of recently adopted orphan receptors for apelin, urotensin II, and ghrelin identified using novel radioligands and functional role in the human cardiovascular system.
Using novel synthetic radioligands, we have discovered receptors for the recently paired apelin (APJ orphan receptor), ghrelin (GHS orphan receptor), and urotensin II (orphan GPR14) in the human cardiovascular system and determined their anatomical localisation. In addition, we have established functional vasoactive properties for these three peptides as potential vasoconstrictor/vasodilator mediators and provided evidence for alteration of receptor density in cardiovascular disease. We find that receptors for apelin, ghrelin, and urotensin II are widely distributed in human cardiovascular tissue, suggesting perhaps vasoactive roles for these peptides in human vascular physiology and a potential role in pathophysiology. Apelin and urotensin II are potent vasoconstrictors with low efficacy, consistent with their low receptor density. Ghrelin receptor density was increased (approximately three- to fourfold) with atherosclerosis of coronary artery disease and accelerated atherosclerosis of saphenous vein grafts, compared with normal vessels, highlighting a potentially beneficial role for this novel vasodilator peptide in human vascular disease. Our approach has demonstrated one successful strategy for translating genetic information encoding recently paired orphan receptor ligands into discovery of function. This study has the advantage of focussing on the actual disease processes, which allow the more precise identification of novel therapeutic targets.
Katugampola
S D
SD
University of Cambridge, Centre for Clinical Investigation, Addenbrooke's Hospital, UK.
Maguire
J J
JJ
Kuc
R E
RE
Wiley
K E
KE
Davenport
A P
AP
D000595:Amino Acid Sequence / Q000502:physiology; D000818:Animals; D000075244:Apelin Receptors; D002318:Cardiovascular Diseases / Q000235:genetics / Q000378:metabolism; D002319:Cardiovascular System / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D011869:Radioligand Assay / Q000379:methods / Q000706:statistics & numerical data; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled; D054440:Receptors, Ghrelin
C104575:APLNR protein, human; D000075244:Apelin Receptors; D011956:Receptors, Cell Surface; D017448:Receptors, Dopamine D2; D043562:Receptors, G-Protein-Coupled; D054440:Receptors, Ghrelin; C121697:UTS2R protein, human