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β2-Adrenergic Regulation of the Neuromuscular Transmission and Its Lipid-Dependent Switch

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Abstract

β2-Adrenoceptors (β2-ARs) are the most abundant subtype of adrenergic receptors in skeletal muscles. Their activation via a stabilization of postsynaptic architecture has beneficial effects in certain models of neuromuscular disorders. However, the ability of β2-ARs to regulate neuromuscular transmission at the presynaptic level is poorly understood. Using electrophysiological recordings and fluorescent FM dyes, we found that β2-AR activation with fenoterol enhanced an involvement of synaptic vesicles in exocytosis and neurotransmitter release during intense activity at the neuromuscular junctions of mouse diaphragm. This was accompanied by an improvement of contractile responses to phrenic nerve stimulation (but not direct stimulation of the muscle fibers) at moderate-to-high frequencies. β2-ARs mainly reside in lipid microdomains enriched with cholesterol and sphingomyelin. The latter is hydrolyzed by sphingomyelinases, whose upregulation occurs in many conditions characterized by muscle atrophy and sympathetic nerve hyperactivity. Sphingomyelinase treatment reversed the effects of β2-AR agonist on the neurotransmitter release and synaptic vesicle recruitment to the exocytosis during intense activity. Inhibition of Gi protein with pertussis toxin completely prevented the sphingomyelinase-mediated inversion in the β2-AR agonist action. Note that lipid raft disrupting enzyme cholesterol oxidase had the same effect on β2-AR agonist-mediated changes in neurotransmission as sphingomyelinase. Thus, β2-AR agonist fenoterol augmented recruitment and release of synaptic vesicles during intense activity in the diaphragm neuromuscular junctions. Sphingomyelin hydrolysis inversed the effects of β2-AR agonist on neurotransmission probably via switching to Gi protein-dependent signaling. This phenomenon may reflect a dependence of the β2-AR signaling on lipid raft integrity in the neuromuscular junctions.

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Data Availability

All mentioned data are represented in the main manuscript figures and supplementary figures. Other additional data will be made available on reasonable request.

Abbreviations

ACh:

Acetylcholine

β2-AR:

Beta2-adrenoceptor

ChO:

Cholesterol oxidase

EPP:

Endplate potential

MEPP:

Miniature endplate potential

NMJ:

Neuromuscular junction

nAChR:

Nicotinic acetylcholine receptor

PTX:

Pertussis toxin

SMase:

Sphingomyelinase

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Acknowledgements

ANT was supported by assignment for Kazan Institute of Biochemistry and Biophysics, FRC Kazan Scientific Center of Russian Academy of Sciences.

Funding

This work was supported by the Russian Science Foundation (grant numbers 21–14-00044, https://rscf.ru/project/21-14-00044/ (#3.3–3.6 Result’s sections); 23–15-00124, https://www.rscf.ru/project/23-15-00124/ (#3.1 and 3.2 Result’s sections); and 23–75-10022, https://www.rscf.ru/project/23-75-10022/ (#3.7 Result’s section)).

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Authors and Affiliations

  1. Laboratory of Biophysics of Synaptic Processes, Kazan Institute of Biochemistry and Biophysics, FRC Kazan Scientific Center of RAS, 2/31 Lobachevsky St., Kazan, RT, Russia, 420111

    Chulpan R. Gafurova, Andrei N. Tsentsevitsky, Nikita S. Fedorov, Arthur N. Khaziev, Artem I. Malomouzh & Alexey M. Petrov

  2. Kazan State Medical University, 49 Butlerova St., Kazan, RT, Russia, 420012

    Chulpan R. Gafurova & Alexey M. Petrov

  3. Kazan National Research Technical University, 10, K. Marx St., Kazan, Russia, 420111

    Artem I. Malomouzh

  4. Kazan Federal University, 18 Kremlyovskaya St., Kazan, Russia, 420008

    Alexey M. Petrov

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  1. Chulpan R. Gafurova
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  2. Andrei N. Tsentsevitsky
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  3. Nikita S. Fedorov
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  4. Arthur N. Khaziev
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  5. Artem I. Malomouzh
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  6. Alexey M. Petrov
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Contributions

ANT: electrophysiological experiments, visualization, and data analysis, review and editing; CRG: fluorescent experiments, visualization, and data analysis; NSF: contraction recording and data analysis; AIM: visualization, review and editing; ANK: electrophysiological data analysis; AMP: conceptualization; writing, review, and editing. All authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Alexey M. Petrov.

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Ethics Approval

The experimental protocol met the requirements of the EU Directive 2010/63/EU and was approved by the Local Ethical Committee of Kazan Federal Scientific Centre (#23/7; May 12, 2023) and Kazan Medical University (Protocol #1/January 25, 2022). The current study was conducted in compliance with the NIH Guide for the Care and Use of Laboratory Animals. Research does not involve human patients.

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Chulpan R Gafurova and Andrei N. Tsentsevitsky are first coauthors with equal contribution.

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Gafurova, C.R., Tsentsevitsky, A.N., Fedorov, N.S. et al. β2-Adrenergic Regulation of the Neuromuscular Transmission and Its Lipid-Dependent Switch. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-03991-2

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