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4-Aminopyridine activates calcium influx through modulation of the pore-forming purinergic receptor in human peripheral blood mononuclear cells

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Abstract:

We investigated whether 4-aminopyridine (4AP), a drug recently linked to calcium influx and apoptosis, also affected purinergic receptor channels that are known to play an important role in the activation of T lymphocytes. The application of 4AP induced a rise in [Ca2+]i that was sensitive to nickel. This action was also observed in cells in which calcium reserves were emptied using thapsigargin (Tg). However, it was not present in the absence of extracellular Ca2+, despite full internal reserves. Adenosine trisphosphate (ATP), a partial agonist and a physiological activator of purinergic receptors, also stimulated Ca2+ entry independently of the calcium release from internal compartments. The effects of 4AP and ATP were not additive when studied on the same population of cells. KN-62 inhibited an increase in calcium entry induced by 4AP, while brilliant blue G (BBG) prevented it, supporting the hypothesis that purinergic P2X7 receptors are involved in this action. Furthermore, 4AP allowed entry of ethidium bromide (314 Da) but not propidium iodide (415 Da) into the cell, also corroborating the involvement of P2X7 pores. The presented results demonstrate, for the first time in human mononuclear cells isolated from healthy volunteers, that the P2X7 channel pore is involved in the action of 4AP and intervenes in the sustained calcium entry induced in response to 4AP.Key words: calcium, human lymphocytes, 4-aminopyridine, purinergic receptors.

Nous avons examiné si la 4-aminopyridine (4AP), le médicament récemment lié à l'influx calcique et à l'apoptose, a aussi une incidence sur les canaux des récepteurs purinergiques qui sont connus pour jouer un rôle important dans l'activation des lymphocytes T. L'application de 4AP a provoqué une élévation de la [Ca2+]i qui était sensible au nickel. Cette action a aussi été observée dans les cellules où les réserves de calcium ont été éliminées en utilisant de la thapsigargine (Tg). Toutefois, elle a disparu en l'absence de Ca2+ extracellulaire, malgré des réserves internes intactes. L'adénosine trisphosphate (ATP), un agoniste partiel et activateur physiologique des récepteurs purinergiques, a aussi stimulé l'entrée de Ca2+, indépendamment de la libération de calcium des compartiments internes. Les effets de la 4AP et de l'ATP sur la même population de cellules n'ont pas été additifs. Le KN-62 a inhibé l'augmentation de l'entrée de calcium induite par la 4AP, alors que le bleu de Coomassie brillant G (BBG) l'a prévenue, venant étayer l'hypothèse que les récepteurs purinergiques P2X7 jouent un rôle dans cette action. De plus, la 4AP a permis l'entrée de bromure d'éthidium (314 Da), mais pas d'iodure de propidium (415 Da), dans la cellule, ce qui a aussi corroboré la participation du pore P2X7. Ces résultats démontrent, pour la première fois dans les cellules mononucléaires humaines isolée de volontaires en santé, que le pore des canaux P2X7 joue participe à l'action de la 4AP et joue un rôle dans l'entrée soutenue de calcium induite par la 4AP.Mots clés : calcium, lymphocytes humains, 4-aminopyridine, récepteur purinergique.

Document Type: Research Article

Publication date: January 1, 2004

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