title: High constitutive signaling of the ghrelin receptor--identification of a potent inverse agonist.
abstract: Ghrelin is a GH-releasing peptide that also has an important role as an orexigenic hormone-stimulating food intake. By measuring inositol phosphate turnover or by using a reporter assay for transcriptional activity controlled by cAMP-responsive elements, the ghrelin receptor showed strong, ligand-independent signaling in transfected COS-7 or human embryonic kidney 293 cells. Ghrelin and a number of the known nonpeptide GH secretagogues acted as agonists stimulating inositol phosphate turnover further. In contrast, the low potency ghrelin antagonist, [D-Arg1,D-Phe5,D-Trp7,9,Leu11]-substance P was surprisingly found to be a high potency (EC50 = 5.2 nm) full inverse agonist as it decreased the constitutive signaling of the ghrelin receptor down to that observed in untransfected cells. The homologous motilin receptor functioned as a negative control as it did not display any sign of constitutive activity; however, upon agonist stimulation the motilin receptor signaled as strongly as the unstimulated ghrelin receptor. It is concluded that the ghrelin receptor is highly constitutively active and that this activity could be of physiological importance in its role as a regulator of both GH secretion and appetite control. It is suggested that inverse agonists for the ghrelin receptor could be particularly interesting for the treatment of obesity.
authors.affiliation: Laboratory for Molecular Pharmacology, Institute of Pharmacology, The Panum Institute, University of Copenhagen, DK-2200 Copenhagen, Denmark. b.holst@molpharm.dk.
authors.forename: Birgitte
authors.initials: B
authors.lastname: Holst
authors.forename: Adam
authors.initials: A
authors.lastname: Cygankiewicz
authors.forename: Tine Halkjaer
authors.initials: TH
authors.lastname: Jensen
authors.forename: Michael
authors.initials: M
authors.lastname: Ankersen
authors.forename: Thue W
authors.initials: TW
authors.lastname: Schwartz
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D054439:Ghrelin; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D008024:Ligands; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009765:Obesity / Q000378:metabolism; D036361:Peptide Hormones / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D054440:Receptors, Ghrelin; D020218:Response Elements / Q000235:genetics; D015398:Signal Transduction; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D054439:Ghrelin; D007295:Inositol Phosphates; D008024:Ligands; D036361:Peptide Hormones; D043562:Receptors, G-Protein-Coupled; D054440:Receptors, Ghrelin; D010738:Type C Phospholipases