Adenosine is an agonist of the growth hormone secretagogue receptor

Growth hormone secretagogues (GHSs) are synthetic compounds that induce GH release in several species, including man. The aim of the current study was to identify hypothalamic GHS receptor (GHS-R) agonists. This led to the di scovery of adenosine as a GHS-R agonist. We demonstrate that adenosine as w ell as the A1 adenosine receptor agonist N-6-R-phenylisopropyladenosine (R- PIA) induce calcium responses, with EC50 values of 50 nM and 0.5 nM, respec tively, in cells which express recombinant human GHS-R. However, neither co mpound induces a calcium response in nontransfected cells. Binding experime nts show that adenosine and the GHS compound MK-0677 bind to membranes from GHS-R expressing cells with nearly identical B-max values (2.6 +/- 0.1 . 1 0(-10) mol/mg protein for adenosine and 2.0 +/- 0.3 . 10(-10) mol/mg protei n for MK-0677). However, no binding to membranes from nontransfected cells could be detected. Furthermore, we show that the IC50 values for inhibition of the adenosine, R-PIA, and GHS induced calcium responses by the GHS-R an tagonist [D-Arg(1), D-Phe(5), D-Trp(7,9), D-Leu(11)]-substance P are simila r. These findings strongly suggest that adenosine and R-PLA are agonists of the GHS-R. Interestingly, neither adenosine nor R-PIA were able to induce GH release from rat pituitary cells in vitro. The implications of the latte r finding is discussed.