Nitric oxide stimulates IP3 production via a cGMP/ PKG-dependent pathway in rat pancreatic acinar cells
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In an attempt to explore the functioning of nitric oxide (NO) in pancreatic exocrine cells,we have recently obtained several lines of circumstantial evidence indicating that one ofmolecular targets of NO is phospholipase C (PLC), the activation of which leads to anincrease in the cytosolic Ca2＋ concentration ([Ca2＋]i) via inositol 1, 4, 5-trisphosphate, IP3.However, whether IP3 is actually produced by NO has not yet been substantiated. Thepresent study was therefore designed to directly measure the intracellular IP3concentration ([IP3]i) for better understanding of the underlying mechanisms with the helpof pharmacological tools. [IP3]i was measured using a fluorescence polarization technique(HitHunter™). We obtained the following results: 1) varying concentrations of an NO donor,sodium nitroprusside (SNP), elevated [IP3]i, 2) this elevation was completely inhibited inthe presence of the soluble guanylyl cyclase (sGC) inhibitor, 1H-[1, 2, 4] oxadiazolo [4, 3-a]quinoxalin-1-one (ODQ), 3) varying concentrations of the cGMP analogue, 8-Br-cGMP, alsoincreased [IP3]i, 4) the cGMP analogue-induced IP3 production was abolished bypretreatment with either a PLC inhibitor, U73122, or a G-protein inhibitor, GP2A, and 5)KT5823, a potent and highly selective inhibitor of cGMP-dependent protein kinase G (PKG),also abolished the IP3 production induced by 8-Br-cGMP. These results suggest that theNO-induced [Ca2＋]i increase is triggered by an increase in [IP3]i located downstream fromintracellular cGMP elevation. In this intracellular pathway, each sGC, cGMP-dependentPKG, G-protein and PLC were suggested to be involved. The present work provides newinsights into the intracellular signaling accelerated by NO. NO triggers a [Ca2＋]i increasevia cGMP and IP3 in pancreatic acinar cells.
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