期刊
JOURNAL OF PHYSIOLOGICAL SCIENCES
卷 57, 期 2, 页码 85-94出版社
PHYSIOLOGICAL SOCIETY JAPAN
DOI: 10.2170/physiolsci.RP011406
关键词
Cl- current; ventricular cell; P2Y receptor; CFTR; ATP hydrolysis
类别
The intracellular signaling pathways responsible for extracellualr uridine-5'-triphosphate (UTP,))-induced chloride (Cl-) currents ((/)(CI.UTP)) were studied in mouse ventricular myocytes with the whole-cell clamp technique. UTP, (0.1 to 100 lam) 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-1 72, 10 pm) of cystic fibrosis transmembrane conductance regulator (CFTR), but not by a disulfonic stilbene derivative (DIDS, 100 tm), 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 tm), a P2Y receptor antagonist, strongly inhibited the UTPo-activation of the Cl- current, where- as pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS, 100 mu m), another P2Y receptor antagonist, induced little inhibition of (/)(CI.UTP) The activation of /(CI.UTP) was sensitive to protein kinase C (PKC) inhibitor, phospholipase C (PLC) inhibitor, intracellular GDP beta S (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. (/)(CI.UTP) was persistently activated with a mixture of ATP gamma S + ATP in the pipette, suggesting the involvement of phosphorylation reaction in the current activation process. Our results strongly suggest that (/)(CI.UTP) is due to the activation of CFTR Cl- channels through Gq/11-coupled P2Y(2) receptor-PLC-PKC signaling and ATP hydrolysis in mouse heart.
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