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Adenosine Is an Agonist of the Growth Hormone Secretagogue Receptor

Health Care Discovery, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark

Address all correspondence and requests for reprints to: Søren Tullin, Health Care Discovery, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark. E-mail: stu{at}novo.dk

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 discovery of adenosine as a GHS-R agonist. We demonstrate that adenosine as well as the A1 adenosine receptor agonist N⁶-R-phenylisopropyladenosine (R-PIA) induce calcium responses, with EC₅₀ values of 50 nM and 0.5 nM, respectively, in cells which express recombinant human GHS-R. However, neither compound induces a calcium response in nontransfected cells. Binding experiments 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 ± 0.1·10^-10 mol/mg protein for adenosine and 2.0 ± 0.3·10^-10 mol/mg protein for MK-0677). However, no binding to membranes from nontransfected cells could be detected. Furthermore, we show that the IC₅₀values for inhibition of the adenosine, R-PIA, and GHS induced calcium responses by the GHS-R antagonist [D-Arg¹, D-Phe⁵, D-Trp^7,9, D-Leu¹¹]-substance P are similar. These findings strongly suggest that adenosine and R-PIA 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 latter finding is discussed.

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