Inhibition of glucose stimulated insulin secretion by neuropeptide Y is mediated via the Y1 receptor and inhibition of adenylyl cyclase in RIN 5AH rat insulinoma cells.
Neuropeptide Y (NPY) has been shown to inhibit insulin secretion from the islets of Langerhans. We show that insulin secretion in the insulinoma cell line RIN 5AH is inhibited by NPY. 125I-Peptide YY (PYY) saturation and competition-binding studies using NPY fragments and analogues on membranes prepared from this cell line show the presence of a single class of NPY receptor with a Y1 receptor subtype-like profile. Inhibition of insulin secretion in this cell line by NPY fragments and analogues also shows a Y1 receptor-like profile. Both receptor binding and inhibition of insulin secretion showed the same orders of potency with NPY > [Pro34]-NPY > NPY 3-36 >> NPY 13-36. The Y1 receptor antagonist, BIBP 3226, blocks NPY inhibition of insulin secretion from, and inhibits 125I-PYY binding to, RIN 5AH cells. Northern blot analysis using a Y1-receptor specific probe shows that NPY Y1 receptors are expressed by RIN 5AH cells. Y5 receptors are not expressed in this cell line. Neuropeptide Y inhibition of insulin secretion is blocked by incubation with pertussis toxin, implying that the effect is via a G-protein (Gi or Go) coupled receptor. Neuropeptide Y inhibits the activation of adenylyl cyclase by isoprenaline in RIN 5AH cell lysates, and the stimulation of cAMP by glucagon-like peptide-1 (7-36) amide (GLP-1). It also blocks insulin secretion stimulated by GLP-1, but not by dibutyryl cyclic AMP. Hence, we suggest that NPY inhibits insulin secretion from RIN 5AH cells via a Y1 receptor linked through Gi to the inhibition of adenylyl cyclase.
Morgan
D G
DG
ICSM Endocrine Unit at the Hammersmith Hospital, Imperial College School of Medicine, London, UK.
Kulkarni
R N
RN
Hurley
J D
JD
Wang
Z L
ZL
Wang
R M
RM
Ghatei
M A
MA
Karlsen
A E
AE
Bloom
S R
SR
Smith
D M
DM
D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D015152:Blotting, Northern; D000242:Cyclic AMP / Q000378:metabolism; D005934:Glucagon / Q000494:pharmacology; D052216:Glucagon-Like Peptide 1; D005947:Glucose / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007340:Insulinoma / Q000503:physiopathology*; D007457:Iodine Radioisotopes; D007545:Isoproterenol / Q000494:pharmacology; D009478:Neuropeptide Y / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000503:physiopathology*; D010446:Peptide Fragments / Q000494:pharmacology; D019894:Peptide YY / Q000378:metabolism; D011498:Protein Precursors / Q000494:pharmacology; D051381:Rats; D017476:Receptors, Neuropeptide Y / Q000502:physiology*; D013552:Swine; D014407:Tumor Cells, Cultured
D000067956:Adenylyl Cyclase Inhibitors; D007328:Insulin; D007457:Iodine Radioisotopes; D009478:Neuropeptide Y; D010446:Peptide Fragments; D011498:Protein Precursors; D017476:Receptors, Neuropeptide Y; D019894:Peptide YY; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D005947:Glucose; D007545:Isoproterenol