title: Adenosine is an agonist of the growth hormone secretagogue receptor.
abstract: 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 Bmax values (2.6 +/- 0.1 x 10(-10) mol/mg protein for adenosine and 2.0 +/- 0.3 x 10(-10) mol/mg protein 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 antagonist [D-Arg1, D-Phe5, D-Trp7,9, 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.
authors.affiliation: Health Care Discovery, Novo Nordisk A/S, Novo Nordisk Park, Måløv, Denmark. stu@novo.dk
authors.forename: S
authors.initials: S
authors.lastname: Tullin
authors.forename: B S
authors.initials: BS
authors.lastname: Hansen
authors.forename: M
authors.initials: M
authors.lastname: Ankersen
authors.forename: J
authors.initials: J
authors.lastname: Møller
authors.forename: K A
authors.initials: KA
authors.lastname: Von Cappelen
authors.forename: L
authors.initials: L
authors.lastname: Thim
mesh_terms: D000241:Adenosine / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D005260:Female; D005456:Fluorescent Dyes; D016257:Fura-2; D013006:Growth Hormone / Q000378:metabolism*; D006801:Humans; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D010902:Pituitary Gland / Q000166:cytology / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011955:Receptors, Drug / Q000819:agonists* / Q000235:genetics; D013056:Spectrophotometry, Ultraviolet; D013141:Spiro Compounds / Q000494:pharmacology; D014162:Transfection
chemical_list: D005456:Fluorescent Dyes; D007211:Indoles; D011955:Receptors, Drug; D013141:Spiro Compounds; D013006:Growth Hormone; D000241:Adenosine; C094817:ibutamoren mesylate; D002118:Calcium; D016257:Fura-2