Adenosine: A partial agonist of the growth hormone secretagogue receptor

The growth hormone secretagogue receptor (GHS-R) is involved in the regulat ion of pulsatile GH release. However, until recently, natural endogenous li gands for the receptor were unknown. We fractionated porcine hypothalamic e xtracts and assayed fractions for activity on HEK293 cells expressing GHS-R and aequorin. A partial agonist was isolated and identified using microspr ay tandem mass spectrometry as adenosine. GHS-R activation by adenosine and synthetic adenosine agonists is inhibited by the GHS-R selective antagonis ts L-765,867, D-Lys(3)-GHRP-6, and by theophylline and XAC. Cross desensiti zation of the GHS-R occurs with both MK-0677 and adenosine. Ligand binding and site directed mutagenesis studies show that adenosine binds to a bindin g site that is distinct from the previously characterized MK-0677 and GHRP- 6 binding pocket. We propose, that adenosine is a physiologically important endogenous GHS-R ligand and speculate that GHS-R Ligands modulate dopamine release from hypothalamic neurons. (C) 2000 Academic Press.