Ligand Activation Domain of Human Orphan Growth Hormone (GH) Secretagogue Receptor (GHS-R) Conserved from Pufferfish to Humans

• DOI: 10.1210/mend.14.1.0412
• Publication Date: 2014-01-08T12:30:14Z
• Authors: Oksana C. Palyha; Scott D. Feighner; Carina P. Tan; Karen Kulju McKee; Donna L. Hreniuk; Ying-Duo Gao; Klaus D. Schleim; Lihu Yang; Gregori J. Morriello; Ravi Nargund; Arthur A. Patchett; Andrew D. Howard; Roy G. Smith
• Keywords: Orphan receptor; Secretagogue

Synthetic ligands have been identified that reset and amplify the cycle of pulsatile GH secretion by interacting with orphan GH-secretagogue receptor (GHS-R). The GHS-R is rhodopsin like, but does not obviously belong to any established G protein-coupled (GPCR) subfamilies. We recently characterized closely related family member, GPR38, as motilin receptor. A common property both receptors they sustain biological responses in continued presence their respective ligands. To efficiently identify additional members this new GPCR family, we explored a vertebrate species having compact genome, was evolutionary distant from human, where functionally important genes were likely be conserved. Accordingly, three distinct full-length clones, encoding proteins significant identity human GHS-R, isolated Pufferfish (Spheroides nephelus). Southern analyses showed cloned are highly conserved across species. gene closest (58%) activated synthetic chosen for very high selectivity on illustrated specificity activating wild-type E124Q mutant. These results indicate ligand activation domain has (400 million years), supporting notion its natural play fundamentally role biology. Furthermore, illustrate power exploiting genome simplifying isolation endocrinologically families.