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Hence, we investigated the effect of inosine on spontaneous and evoked ACh<\/jats:styled-content> release, the mechanism underlying its modulatory action and the receptor type and signal transduction pathway involved.<\/jats:p><\/jats:sec>Experimental Approach<\/jats:title>End\u2010plate potentials (EPPs<\/jats:styled-content>) and miniature end\u2010plate potentials (MEPPs<\/jats:styled-content>) were recorded from the mouse phrenic\u2010nerve diaphragm preparations using conventional intracellular electrophysiological techniques.<\/jats:p><\/jats:sec>Key Results<\/jats:title>Inosine (100\u2009\u03bcM) reduced MEPP<\/jats:styled-content> frequency and the amplitude and quantal content of EPPs<\/jats:styled-content>; effects inhibited by the selective A3<\/jats:sub><\/jats:styled-content> receptor antagonist MRS<\/jats:styled-content>\u20101191. Immunohistochemical assays confirmed the presence of A3<\/jats:sub><\/jats:styled-content> receptors at mammalian NMJ<\/jats:styled-content>. The voltage\u2010gated calcium channel (VGCC<\/jats:styled-content>) blocker Cd2+<\/jats:sup><\/jats:roman><\/jats:styled-content>, the removal of extracellular Ca2+<\/jats:sup><\/jats:roman><\/jats:styled-content> and the L<\/jats:styled-content>\u2010type and P\/Q<\/jats:styled-content>\u2010type VGCC<\/jats:styled-content> antagonists, nitrendipine and \u03c9\u2010agatoxin IVA,<\/jats:styled-content> respectively, all prevented inosine\u2010induced inhibition. In the absence of endogenous adenosine, inosine decreased the hypertonic response. The effects of inosine on ACh release were prevented by the Gi\/o<\/jats:sub><\/jats:styled-content> protein inhibitor N<\/jats:styled-content>\u2010ethylmaleimide, PKC<\/jats:styled-content> antagonist chelerytrine and calmodulin antagonist W<\/jats:styled-content>\u20107, but not by PKA<\/jats:styled-content> antagonists, H<\/jats:styled-content>\u201089 and KT<\/jats:styled-content>\u20105720, or the inhibitor of CaMKII KN<\/jats:styled-content>\u201062.<\/jats:p><\/jats:sec>Conclusion and Implications<\/jats:title>Our results suggest that, at motor nerve terminals, inosine induces presynaptic inhibition of spontaneous and evoked ACh<\/jats:styled-content> release by activating A3<\/jats:sub><\/jats:styled-content> receptors through a mechanism that involves L<\/jats:styled-content>\u2010type and P\/Q<\/jats:styled-content>\u2010type VGCCs<\/jats:styled-content> and the secretory machinery downstream of calcium influx. A3<\/jats:sub><\/jats:styled-content> receptors appear to be coupled to Gi\/o<\/jats:sub><\/jats:styled-content> protein. PKC<\/jats:styled-content> and calmodulin may be involved in these effects of inosine.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.12262","type":"journal-article","created":{"date-parts":[[2013,6,3]],"date-time":"2013-06-03T16:43:18Z","timestamp":1370277798000},"page":"1810-1823","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Inosine induces presynaptic inhibition of acetylcholine release by activation of A3<\/sub><\/scp> adenosine receptors at the mouse neuromuscular junction"],"prefix":"10.1111","volume":"169","author":[{"given":"A R","family":"Cinalli","sequence":"first","affiliation":[{"name":"Laboratorio de Neurofisiolog\u00eda Instituto de Investigaciones M\u00e9dicas Alfredo Lanari Universidad de Buenos Aires \u2013 Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas (CONICET) Buenos Aires Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J 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