Adenosine Discovered as Natural Regulator of Growth Hormone Receptor

The growth hormone secretagogue receptor (GHS-R) plays a crucial role in regulating pulsatile GH release (growth hormone), which is essential for growth, metabolism, and body composition. Despite its known importance, the natural endogenous ligands—molecules produced within the body that activate this receptor—were previously unknown, leaving a significant gap in our understanding of its physiological control.

The study successfully identified adenosine as a partial agonist of the GHS-R, meaning it can activate the receptor but not to its full potential. Activation of GHS-R by adenosine was significantly inhibited by selective GHS-R antagonists, including L-765,867, D-Lys(3)-GHRP-6, theophylline, and XAC, confirming its specific interaction with the receptor. They also observed cross-desensitization of the GHS-R with both MK-0677 and adenosine, suggesting that despite potentially different binding sites, they share some common downstream signaling pathways. > Crucially, ligand binding and site-directed mutagenesis studies revealed that adenosine binds to a distinct binding site on the GHS-R, separate from the previously characterized binding pockets for MK-0677 and GHRP-6, indicating a novel and complex regulatory mechanism for GHS-R activity. This finding suggests multiple ways the receptor can be modulated.