Imidazoline NNC77-0074 stimulates Ca2+-evoked exocytosis in INS-1E cells by a phospholipase A2-dependent mechanism.
We have previously demonstrated that the novel imidazoline compound (+)-2-(2-(4,5-dihydro-1H-imidazol-2-yl)-thiopene-2-yl-ethyl)-pyridine (NNC77-0074) increases insulin secretion from pancreatic beta-cells by stimulation of Ca(2+)-dependent exocytosis. Using capacitance measurements, we now show that NNC77-0074 stimulates exocytosis in clonal INS-1E cells. NNC77-0074-stimulated exocytosis was antagonised by the cytoplasmic phospholipase A(2) (cPLA(2)) inhibitors ACA and AACOCF(3) and in cells treated with antisense oligonucleotide against cPLA(2)alpha. NNC77-0074-evoked insulin secretion was likewise inhibited by ACA, AACOCF(3), and cPLA(2)alpha antisense oligonucleotide treatment. In pancreatic islets NNC77-0074 stimulated PLA(2) activity. We propose that cPLA(2)alpha plays an important role in the regulation of NNC77-0074-evoked exocytosis in insulin secreting beta-cells.
Olsen
Hervør L
HL
Novo Nordisk A/S, Novo Allé, Bagsvaerd DK-2880, Denmark. HLOL@novonordisk.com
Nørby
Peder L
PL
Høy
Marianne
M
Spee
Pieter
P
Thams
Peter
P
Capito
Kirsten
K
Petersen
Jacob S
JS
Gromada
Jesper
J
D000818:Animals; D020013:Calcium Signaling; D002478:Cells, Cultured; D004791:Enzyme Inhibitors; D005089:Exocytosis; D054513:Group IV Phospholipases A2; D007093:Imidazoles / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology; D008297:Male; D051379:Mice; D016376:Oligonucleotides, Antisense / Q000235:genetics; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D054467:Phospholipases A2; D011725:Pyridines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
C474118:2-(2-(4,5-dihydro-1H-imidazol-2-yl)thiophene-2-ylethyl)pyridine; D004791:Enzyme Inhibitors; D007093:Imidazoles; D016376:Oligonucleotides, Antisense; D011725:Pyridines; D010741:Phospholipases A; D054513:Group IV Phospholipases A2; D054467:Phospholipases A2