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

2008; American Physical Society; Volume: 295; Issue: 1 Linguagem: Inglês

10.1152/ajpheart.00135.2008

1522-1539

Julio L. Álvarez, Alain Coulombe, Olivier Cazorla, Mehmet Uğur, J. Rauzier, János Magyar, Eve-Lyne Mathieu, Guylain Boulay, Rafael Souto, Patrice Bideaux, Guillermo Salazar, François Rassendren, Alain Lacampagne, Jérémy Fauconnier, Guy Vassort,

Advanced battery technologies research

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 P2Y 2 receptors are involved. I ATP resulted from the binding of ATP 4− to P2Y 2 purinoceptors. I ATP was maintained after ATP removal in the presence of guanosine 5′-[γ-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, Mn 2+ quenching and Ba 2+ 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 P2Y 2 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.