Adenosine: A partial agonist of the growth hormone secretagogue receptor.
The growth hormone secretagogue receptor (GHS-R) is involved in the regulation of pulsatile GH release. However, until recently, natural endogenous ligands for the receptor were unknown. We fractionated porcine hypothalamic extracts and assayed fractions for activity on HEK293 cells expressing GHS-R and aequorin. A partial agonist was isolated and identified using microspray tandem mass spectrometry as adenosine. GHS-R activation by adenosine and synthetic adenosine agonists is inhibited by the GHS-R selective antagonists L-765,867, D-Lys(3)-GHRP-6, and by theophylline and XAC. Cross desensitization of the GHS-R occurs with both MK-0677 and adenosine. Ligand binding and site directed mutagenesis studies show that adenosine binds to a binding 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.
Smith
R G
RG
Huffington Center on Aging, Baylor College of Medicine, Houston, Texas, USA. rsmith@bcm.tmc.edu
Griffin
P R
PR
Xu
Y
Y
Smith
A G
AG
Liu
K
K
Calacay
J
J
Feighner
S D
SD
Pong
C
C
Leong
D
D
Pomés
A
A
Cheng
K
K
Van der Ploeg
L H
LH
Howard
A D
AD
Schaeffer
J
J
Leonard
R J
RJ
D000241:Adenosine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D019830:Adenosine-5'-(N-ethylcarboxamide) / Q000494:pharmacology; D000331:Aequorin / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D002457:Cell Extracts; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D004298:Dopamine / Q000378:metabolism; D006801:Humans; D007031:Hypothalamus / Q000166:cytology / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology; D008024:Ligands; D008163:Luminescent Measurements; D013058:Mass Spectrometry; D008954:Models, Biological; D016297:Mutagenesis, Site-Directed; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled; D054440:Receptors, Ghrelin; D013141:Spiro Compounds / Q000494:pharmacology; D013552:Swine; D013806:Theophylline / Q000494:pharmacology
D002457:Cell Extracts; D007211:Indoles; D008024:Ligands; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D054440:Receptors, Ghrelin; D013141:Spiro Compounds; C084956:N(6)-(3-iodobenzyl)-5'-N-methylcarboxamidoadenosine; D019830:Adenosine-5'-(N-ethylcarboxamide); D000331:Aequorin; D013806:Theophylline; D000241:Adenosine; C094817:ibutamoren mesylate; D004298:Dopamine