Ghrelin and its receptor are important regulators of metabolic functions, including appetite, energy expenditure, fat accumulation, and
growth hormone (GH) secretion. The
ghrelin receptor is characterized by an ability to signal even without any
ligand present with approximately 50% of the maximally
ghrelin-induced efficacy-a feature that may have important physiological implications. The high basal signaling can be modulated either by administration of specific
ligands or by engineering of mutations in the receptor structure. [D-Arg(1), D-Phe(5), D-Trp(7,9), Leu(11)]-
substance P was the first inverse agonist to be identified for the
ghrelin receptor, and this
peptide has been used as a starting point for identification of the structural requirements for inverse agonist properties in the
ligand. The receptor binding core motif was identified as D-Trp-Phe-D-
Trp-Leu-Leu, and elongation of this
peptide in the amino-terminal end determined the efficacy. Attachment of a positively charged
amino acid was responsible for full inverse agonism, whereas an alanin converted the
peptide into a partial agonist. Importantly, by use of mutational mapping of the residues critical for the modified D-Trp-Phe-D-
Trp-Leu-Leu
peptides, it was found that space-generating mutations in the deeper part of the receptor improved inverse agonism, whereas similar mutations located in the more extracellular part improved agonism. Modulation of the basal signaling by mutations in the receptor structure is primarily obtained by substitutions in an aromatic cluster that keep TMs VI and VII in close proximity to TM III and thus stabilize the active conformation. Also, substitution of a Phe in TM V is crucial for the high basal activity of the receptor as this residue serves as a partner for Trp VI:13 in the active conformation. It is suggested that inverse agonist and antagonist against the
ghrelin receptor provide an interesting possibility in the development of drugs for treatment of
obesity and diabetes and that improved structural understanding of the receptor function facilitates the
drug development.