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This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 565/1/229    most recent jphysiol.2005.084186v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Giniatullin, A. R. Articles by Giniatullin, R. A. Search for Related Content PubMed PubMed Citation Articles by Giniatullin, A. R. Articles by Giniatullin, R. A.

¹ State Medical University, 420012 Kazan, Tatarstan, Russia
² International School for Advanced Studies, 34014 Trieste, Italy

During normal cell metabolism the production of intracellular ATP is associated with the generation of reactive oxygen species (ROS), which appear to be important signalling molecules. Both ATP and ROS can be released extracellularly by skeletal muscle during intense activity. Using voltage clamp recording combined with imaging and biochemical assay of ROS, we tested the hypothesis that at the neuromuscular junction extracellular ATP generates ROS to inhibit transmitter release from motor nerve endings. We found that ATP produced the presynaptic inhibitory action on multiquantal end-plate currents. The inhibitory action of ATP (but not that of adenosine) was significantly reduced by several antioxidants or extracellular catalase, which breaks down H₂O₂. Consistent with these data, the depressant effect of ATP was dramatically potentiated by the pro-oxidant Fe²⁺. Exogenous H₂O₂ reproduced the depressant effects of ATP and showed similar sensitivity to anti- and pro-oxidants. While NO also inhibited synaptic transmission, inhibitors of the NO-producing cascade did not prevent the depressant action of ATP. The ferrous oxidation in xylenol orange assay showed the increase of ROS production by ATP and 2-MeSADP but not by adenosine. Suramin, a non-selective antagonist of P2 receptors, and pertussis toxin prevented the action of ATP on ROS production. Likewise, imaging with the ROS-sensitive dye carboxy-2',7'-dichlorodihydrofluorescein revealed increased production of ROS in the muscle treated with ATP or ADP while UTP or adenosine had no effect. Thus, generation of ROS contributed to the ATP-mediated negative feedback mechanism controlling quantal secretion of ACh from the motor nerve endings.

(Received 31 January 2005; accepted after revision 10 March 2005; first published online 17 March 2005)
Corresponding author R.A. Giniatullin: Neurobiology Sector, SISSA, Via Beirut, 2/4, 34014 Trieste, Italy. Email: rashid{at}sissa.it

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