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Center of Biomedical Research Excellence, Department of Pharmacology, University of Nevada School of Medicine, Reno, NV, USA

The intracellular signalling pathways and molecular mechanisms responsible for P2-purinoceptor-mediated chloride (Cl^–) currents (I_Cl,ATP) were studied in mouse ventricular myocytes. In standard NaCl-containing extracellular solutions, extracellular ATP (100 µM) activated two different currents, I_Cl,ATP with a linear I–V relationship in symmetrical Cl^– solutions, and an inwardly rectifying cation conductance (cationic I_ATP). Cationic I_ATP was selectively inhibited by Gd³⁺ and Zn²⁺, or by replacement of extracellular NaCl by NMDG; I_Cl,ATP was Cl^– selective, and inhibited by replacement of extracellular Cl^– by Asp^–; both currents were prevented by suramin or DIDS pretreatment. In GTPS-loaded cells, I_Cl,ATP was irreversibly activated by ATP, but cationic I_ATP was still regulated reversibly. GDPßS prevented activation of the I_Cl,ATP, even though pertussis toxin pretreatment did not modulate I_Cl,ATP. These results suggest that activation of I_Cl,ATP occurs via a G-protein coupled P2Y purinergic receptor. The I_Cl,ATP persistently activated by GTPS, was inhibited by glibenclamide but not by DIDS, thus exhibiting known pharmacological properties of cystic fibrosis transmembrane conductance regulator (CFTR) Cl^– channels. In ventricular cells of cftr^–/– mice, extracellular ATP activated cationic I_ATP, but failed to activate any detectable I_Cl,ATP. These results provide compelling evidence that activation of CFTR Cl^– channels in mouse heart are coupled to G-protein coupled P2Y purinergic receptors.

(Received 16 December 2003; accepted after revision 13 February 2004; first published online 20 February 2004)
Corresponding author J. R. Hume: Department of Pharmacology/318, University of Nevada School of Medicine, Reno, NV 89557-0046, USA. Email: joeh{at}med.unr.edu

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