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 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.
Tullin
S
S
Health Care Discovery, Novo Nordisk A/S, Novo Nordisk Park, Måløv, Denmark. stu@novo.dk
Hansen
B S
BS
Ankersen
M
M
Møller
J
J
Von Cappelen
K A
KA
Thim
L
L
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
D005456:Fluorescent Dyes; D007211:Indoles; D011955:Receptors, Drug; D013141:Spiro Compounds; D013006:Growth Hormone; D000241:Adenosine; C094817:ibutamoren mesylate; D002118:Calcium; D016257:Fura-2