High Constitutive Signaling of the Ghrelin Receptor—Identification of a Potent Inverse Agonist

Birgitte Holst, Adam Cygankiewicz, Tine Halkjær Jensen, Michael Ankersen, Thue W. Schwartz
2003 Molecular Endocrinology  
Ghrelin is a growth hormone (GH) releasing peptide, which 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 signalling in transfected COS-7 or HEK293 cells. Ghrelin and a number of the known non-peptide GH secretagogues acted as agonists stimulating inositol phosphate turnover
more » ... urther. In contrast, the low potency ghrelin antagonist, [D-Arg 1 ,D-Phe 5 ,D-Trp 7,9 ,Leu 11 ]-substance P was surprisingly found to be a high potency (EC 50 = 5.2 nM) full inverse agonist as it decreased the constitutive signalling of the ghrelin receptor down to that observed in un-transfected 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 un-stimulated 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.
doi:10.1210/me.2003-0069 pmid:12907757 fatcat:5yawaxjzcvctxfekjqzo7dwmzu