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TRANSLATIONAL PHYSIOLOGY

ATP/UTP activate cation-permeable channels with TRPC3/7 properties in rat cardiomyocytes

¹Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 637, Université Montpellier 1, Unité de Formation et de Recherche de Médecine, Centre Hospitalier Universitaire (CHU) Arnaud de Villeneuve, Montpellier, France; ²Laboratorio de Electrofisiología, Instituto de Cardiología, Havana, Cuba; ³INSERM, Unité Mixte de Recherche (UMR) S621, Université Pierre et Marie Curie, CHU Pitié-Salpêtrière, Paris, France; ⁴Department of Physiology, University of Debrecen, Debrecen, Hungary; ⁵Pharmacology, Faculty of Medicine, University of Sherbrooke, Fleurimont, Quebec, Canada; and ⁶Department of Pharmacology, Institut de Génomique Fonctionnelle, Centre National de la Recherche Scientifique UMR 5203, INSERM Unité 661, Université Montpellier I and Université Montpellier II, Montpellier Cedex, France

Submitted 7 February 2008 ; accepted in final form 16 May 2008

Extracellular purines and pyrimidines have major effects on cardiac rhythm and contraction. ATP/UTP are released during various physiopathological conditions, such as ischemia, and despite degradation by ectonucleotidases, their interstitial concentrations can markedly increase, a fact that is clearly associated with arrhythmia. In the present whole cell patch-clamp analysis on ventricular cardiomyocytes isolated from various mammalian species, ATP and UTP elicited a sustained, nonselective cationic current, I_ATP. UDP was ineffective, whereas 2'(3')-O-(4-benzoylbenzoyl)-ATP was active, suggesting that P2Y₂ receptors are involved. I_ATP resulted from the binding of ATP^4– to P2Y₂ purinoceptors. I_ATP was maintained after ATP removal in the presence of guanosine 5'-[-thio]triphosphate and was inhibited by U-73122, a PLC inhibitor. Single-channel openings are rather infrequent under basal conditions. ATP markedly increased opening probability, an effect prevented by U-73122. Two main conductance levels of 14 and 23 pS were easily distinguished. Similarly, in fura-2-loaded cardiomyocytes, Mn²⁺ quenching and Ba²⁺ influx were significant only in the presence of ATP or UTP. Adult rat ventricular cardiomyocytes expressed transient receptor potential channel TRPC1, -3, -4, and -7 mRNA and the TRPC3 and TRPC7 proteins that coimmunoprecipitated. Finally, the anti-TRPC3 antibody added to the patch pipette solution inhibited I_ATP. In conclusion, activation of P2Y₂ receptors, via a G protein and stimulation of PLCβ, induces the opening of heteromeric TRPC3/7 channels, leading to a sustained, nonspecific cationic current. Such a depolarizing current could induce cell automaticity and trigger the arrhythmic events during an early infarct when ATP/UTP release occurs. These results emphasize a new, potentially deleterious role of TRPC channel activation.

purinergic receptor; signal transduction; infarction; arrhythmia