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The effects of brain-derived neurotrophic factor (BDNF) processing by-product BDNF prodomain on the activity of mature neuromuscular junctions (NMJs) were studied in synapses of the mouse diaphragm. The parameters of spontaneous miniature endplate potentials (MEPPs) and evoked endplate potentials (EPPs) were analyzed in presence of BDNF prodomain (1 nM). BDNF prodomain suppressed both spontaneous and evoked acetylcholine (Ach) release: decreased the frequency and amplitude of MEPPs, and the amplitude and quantal content of EPPs. Inhibition of Rho-GDI-associated p75 receptor signaling with TAT-Pep5 peptide or sortilin with its inhibitor AF38469 completely abolished the BDNF prodomain-induced decrease in spontaneous and evoked quantal Ach release. Moreover, the downregulation of Ach induced by BDNF prodomain was prevented by by Rho-associated protein kinase (ROCK) inhibitor Y-27632. Taken together, these data suggest that in mature motor synapses activation of p75-sortilin by BDNF prodomain triggers the Rho-signaling pathway. Tertiapin-Q, a G-protein-coupled inwardly rectifying potassium channels (GIRK) blocker, but not iberiotoxin, a BK-channels blocker, completely prevented the inhibitory effect of BDNF prodomain. SK-channels blocker apamin prevented the inhibitory effect of BDNF prodomain only partially. At the same time, the BDNF prodomain did not show any inhibitory effects in diaphragm motor synapses of pannexin 1 knockout mice, which have impaired purinergic regulation of neuromuscular transmission. The data obtained suggest that there is a previously unknown mechanism for the acute suppression of spontaneous and evoked ACh release in mature motor synapses, which involves the activation of p75 receptors, ROCK and GIRK channels by BDNF prodomain and requires interaction with metabotropic purinoreceptors. In general, our results show that the product of BDNF maturation has inhibitory effects on spontaneous and evoked ACh release in functionally mature neuromuscular junctions, which are mainly opposite to the effects of BDNF. This work was supported by the Russian Science Foundation (Grant N 22-25-00111).