Distinction of NPY receptors in vitro and in vivo. I. NPY-(18-36) discriminates NPY receptor subtypes in vitro.
We studied the possibility of multiple neuropeptide Y (NPY) receptor subtypes. NPY-stimulated Ca2+ mobilization in human erythroleukemia (HEL) cells was used to screen a number of NPY analogues. The potencies of three of these analogues [peptide YY (PYY), [D-Tyr-36]NPY, and NPY-(18-36)] were compared with that of NPY in the following model systems: Ca2+ mobilization and inhibition of adenosine 3',5'-cyclic monophosphate accumulation in HEL cells, potentiation of vasoconstriction in the isolated rabbit ear artery, reduction of cutaneous microvascular perfusion in the rat digit, and inhibition of [3H]serotonin release in rat brain. In each of the five models, PYY was a full agonist that exhibited a similar or slightly higher potency than NPY, whereas [D-Tyr-36]NPY and NPY-(18-36) were partial agonists with lower potencies: NPY-(18-36) had a lower potency and efficacy than [D-Tyr-36]NPY in HEL cells and the rabbit ear artery, but was more effective than [D-Tyr-36]NPY for constricting cutaneous microvasculature and inhibiting serotonin release. Because of its weak partial agonism, we also tested NPY-(18-36) as an antagonist of NPY-stimulated Ca2+ mobilization in HEL cells. NPY-(18-36) shifted the NPY concentration-response curve to the right with a KB affinity value of 297 nM. In summary, [D-Tyr-36]NPY and NPY-(18-36) are partial agonists, the relative potency of which varies between systems. These data demonstrate the presence of multiple NPY receptor subtypes. We propose a modified classification scheme of NPY receptor subtypes.
Michel
M C
MC
Department of Pharmacology, University of California San Diego, La Jolla 92093.
Schlicker
E
E
Fink
K
K
Boublik
J H
JH
Göthert
M
M
Willette
R N
RN
Daly
R N
RN
Hieble
J P
JP
Rivier
J E
JE
Motulsky
H J
HJ
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D004915:Leukemia, Erythroblastic, Acute; D009478:Neuropeptide Y / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D009638:Norepinephrine / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017476:Receptors, Neuropeptide Y; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000378:metabolism*; D012039:Regional Blood Flow / Q000187:drug effects; D012701:Serotonin / Q000378:metabolism; D012867:Skin / Q000098:blood supply; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D009478:Neuropeptide Y; D010446:Peptide Fragments; D017476:Receptors, Neuropeptide Y; D017981:Receptors, Neurotransmitter; D014662:Vasoconstrictor Agents; C059889:neuropeptide Y (18-36); D012701:Serotonin; D000242:Cyclic AMP; D002118:Calcium; D009638:Norepinephrine