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 | Regulation of Extracellular UTP-Activated Cl− Current by P2Y-PLC-PKC Signaling and ATP Hydrolysis in Mouse Ventricular Myocytes
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| | | 1) Department of Physiology, Saga University Faculty of Medicine |
| (Received October 3, 2006)
(Accepted February 8, 2007)
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| Abstract: The intracellular signaling pathways responsible for extracellualr uridine-5'-triphosphate (UTPo)-induced chloride (Cl−) currents (ICl.UTP) were studied in mouse ventricular myocytes with the whole-cell clamp technique. UTPo (0.1 to 100 μM) activated a whole-cell current that showed a time-independent activation, a linear current-voltage relationship in symmetrical Cl− solutions, an anion selectivity of Cl− > iodide > aspartate, and an inhibition by a thiazolidinone-derived specific inhibitor (CFTRinh-172, 10 μM) of cystic fibrosis transmembrane conductance regulator (CFTR), but not by a disulfonic stilbene derivative (DIDS, 100 μM), these properties matching those of CFTR Cl− channels. The potency order of nucleotides for an activation of the Cl− current was UTP = ATP > uridine-5'-diphosphate (UDP) = ADP. Suramin (100 μM), a P2Y receptor antagonist, strongly inhibited the UTPo-activation of the Cl− current, whereas pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS, 100 μM), another P2Y receptor antagonist, induced little inhibition of ICl.UTP. The activation of ICl.UTP was sensitive to protein kinase C (PKC) inhibitor, phospholipase C (PLC) inhibitor, intracellular GDPβS (nonhydrolyzable GDP analogue) or anti-Gq/11 antibody. UTPo failed to activate the Cl− current when the cells were dialyzed with nonhydrolyzable ATP analogues (ATPS or AMP-PNP) without ATP, suggesting that ATP hydrolysis is a prerequisite for the current activation. ICl.UTP was persistently activated with a mixture of ATPγS + ATP in the pipette, suggesting the involvement of phosphorylation reaction in the current activation process. Our results strongly suggest that ICl.UTP is due to the activation of CFTR Cl− channels through Gq/11-coupled P2Y2 receptor-PLC-PKC signaling and ATP hydrolysis in mouse heart.
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| To cite this article: | | Shintaro Yamamoto, Kunihiko Ichishima and Tsuguhisa Ehara: “Regulation of Extracellular UTP-Activated Cl− Current by P2Y-PLC-PKC Signaling and ATP Hydrolysis in Mouse Ventricular Myocytes”, J. Physiol. Sci Vol. 57: 85-94, 2007 . | |
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| doi:10.2170/physiolsci.RP011406 | | JOI JST.JSTAGE/physiolsci/RP011406 |
| Copyright (c) 2007 by The Physiological Society of Japan |
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