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BDNF Prodomain Inhibits Neurotransmitter Quantal Release in Mouse Motor Synapses with the Necessary Participation of Sortilin and Adenosine A1-Receptors

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Abstract

Brain neurotrophin (BDNF) is synthesized by proteolysis of proneurotrophin to form mature BDNF and the prodomain, whose regulatory activity on neuromuscular transmission is just beginning to be studied. At motor synapses, the BDNF prodomain has an inhibitory effect, stimulating GIRK potassium channels via activation of p75 receptors. The aim of this work was to study the initiation and implementation of the mechanism of inhibitory action of the BDNF prodomain in mature motor synapses of the mouse diaphragm. Microelectrodes were used to record spontaneous (miniature) and multiquantal endplate potentials evoked by stimulation of motor axons (MEPPs and EPPs, respectively). Using selective antagonists, it was revealed that the inhibitory effect of the BDNF prodomain on synaptic transmission requires the participation of sortilin, but not TrkB receptors. Stimulation of GIRK induced by the BDNF prodomain requires the participation of synaptic metabotropic receptors, which ensure the action of βγ-subunits of Gi proteins on GIRK. Using selective inhibitors, it was found that M2 cholinergic receptors and P2Y13 purinoceptors negatively regulate presynaptic L-type calcium channels, but these metabotropic receptors are not functionally related to the action of the BDNF prodomain. It turned out that the inhibition of quantal release of acetylcholine in motor synapses caused by BDNF prodomain requires the activity of the adenosine A1-receptors only. In addition, when pannexin 1 was pharmacologically blocked by probenecid, the BDNF prodomain lost its inhibitory effect on neuromuscular transmission. Thus, BDNF prodomain-induced inhibition of quantal neurotransmitter release in mouse motor synapses requires the participation of sortilin and endogenous activation of adenosine A1-receptors, which requires the functioning of pannexins 1, which most likely provide an additional source of synaptic ATP to the vesicular one.

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ACKNOWLEDGMENTS

Some of the equipment used in the experiments was provided by Lomonosov Moscow State University as part of the federal MSU Development Program (contract 0504-44-2023).

Funding

This work was funded by the Russian Science Foundation (project 22-25-00111). No additional grants were received to conduct or supervise this particular study.

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Authors and Affiliations

  1. Lomonosov Moscow State University, Moscow, Russia

    A. I. Molchanova, O. P. Balezina & A. E. Gaydukov

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  1. A. I. Molchanova
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  2. O. P. Balezina
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  3. A. E. Gaydukov
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Contributions

Idea of the work and planning of the experiment (A.E.G.), data collection (A.I.M., A.E.G.), data processing (A.I.M., A.E.G.), manuscript writing and editing (A.I.M., O.P.B., A.E.G.).

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Correspondence to A. E. Gaydukov.

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ETHICS APPROVAL AND CONSENT TO PARTICIPATE

Experiments with animals were conducted in accordance with international recommendations for biomedical research with laboratory animals and were approved by the Bioethical Commission of the Lomonosov Moscow State University (Protocol no. 97-zh-3 of November 11, 2021).

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Molchanova, A.I., Balezina, O.P. & Gaydukov, A.E. BDNF Prodomain Inhibits Neurotransmitter Quantal Release in Mouse Motor Synapses with the Necessary Participation of Sortilin and Adenosine A1-Receptors. J Evol Biochem Phys 60, 363–379 (2024). https://doi.org/10.1134/S0022093024010277

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  • DOI: https://doi.org/10.1134/S0022093024010277

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