TY - JOUR
T1 - High constitutive signaling of the ghrelin receptor--identification of a potent inverse agonist
AU - Holst, Birgitte
AU - Cygankiewicz, Adam
AU - Jensen, Tine Halkjaer
AU - Ankersen, Michael
AU - Schwartz, Thue W
N1 - Keywords: Amino Acid Sequence; Animals; Cell Line; Cercopithecus aethiops; Cyclic AMP Response Element-Binding Protein; Ghrelin; Humans; Inositol Phosphates; Ligands; Molecular Sequence Data; Molecular Structure; Obesity; Peptide Hormones; Receptors, G-Protein-Coupled; Receptors, Ghrelin; Response Elements; Signal Transduction; Type C Phospholipases
PY - 2003
Y1 - 2003
N2 - 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.
AB - 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.
U2 - 10.1210/me.2003-0069
DO - 10.1210/me.2003-0069
M3 - Journal article
C2 - 12907757
SN - 0888-8809
VL - 17
SP - 2201
EP - 2210
JO - Molecular Endocrinology
JF - Molecular Endocrinology
IS - 11
ER -
