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The Mechanism of α2 adrenoreceptor-dependent Modulation of Neurotransmitter Release at the Neuromuscular Junctions

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Abstract

α2-Adrenoreceptors (ARs) are main Gi-protein coupled autoreceptors in sympathetic nerve terminals and targets for dexmedetomidine (DEX), a widely used sedative. We hypothesize that α2-ARs are also potent regulators of neuromuscular transmission via G protein-gated inwardly rectifying potassium (GIRK) channels. Using extracellular microelectrode recording of postsynaptic potentials, we found DEX-induced inhibition of spontaneous and evoked neurotransmitter release as well as desynchronization of evoked exocytotic events in the mouse diaphragm neuromuscular junction. These effects were suppressed by SKF-86,466, a selective α2-AR antagonist. An activator of GIRK channels ML297 had the same effects on neurotransmitter release as DEX. By contrast, inhibition of GIRK channels with tertiapin-Q prevented the action of DEX on evoked neurotransmitter release, but not on spontaneous exocytosis. The synaptic vesicle exocytosis is strongly dependent on Ca2+ influx through voltage-gated Ca2+ channels (VGCCs), which can be negatively regulated via α2-AR – GIRK channel axis. Indeed, inhibition of P/Q-, L-, N- or R-type VGCCs prevented the inhibitory action of DEX on evoked neurotransmitter release; antagonists of P/Q- and N-type channels also suppressed the DEX-mediated desynchronization of evoked exocytotic events. Furthermore, inhibition of P/Q-, L- or N-type VGCCs precluded the frequency decrease of spontaneous exocytosis upon DEX application. Thus, α2-ARs acting via GIRK channels and VGCCs (mainly, P/Q- and N-types) exert inhibitory effect on the neuromuscular communication by attenuating and desynchronizing evoked exocytosis. In addition, α2-ARs can suppress spontaneous exocytosis through GIRK channel-independent, but VGCC-dependent pathway.

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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

AR:

Adrenoceptor

DEX:

Dexmedetomidine

EPP:

End-plate potential

GIRK:

Channel, G Protein-gated inwardly rectifying potassium channel

MEPP:

Miniature end-plate potential

NMJ:

Neuromuscular junction

nAChR:

Nicotinic acetylcholine receptor

TPQ:

Tertiapin-Q

VGCC:

Voltage-gated Ca2+ channel

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Acknowledgements

ANT, VFK were 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 by Russian Science Foundation, grant number [23-15-00124], https://www.rscf.ru/project/23-15-00124/.

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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, 420111, RT, Russia

    Andrei N. Tsentsevitsky, Venera F. Khuzakhmetova, Ellya A. Bukharaeva & Alexey M. Petrov

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

    Alexey M. Petrov

  3. Kazan Federal University, 18 Kremlyovskaya Street, Kazan, 420008, Russia

    Alexey M. Petrov

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  1. Andrei N. Tsentsevitsky
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Contributions

A.T. performed electrophysiological experiments, visualization, and data analysis. V.K. performed electrophysiological experiments. EB was responsible for conceptualization, methodology, project administration, supervision, writing, review & editing; AMP wrote the main text and was responsible for conceptualization, review & editing. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Alexey M. Petrov.

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Tsentsevitsky, A.N., Khuzakhmetova, V.F., Bukharaeva, E.A. et al. The Mechanism of α2 adrenoreceptor-dependent Modulation of Neurotransmitter Release at the Neuromuscular Junctions. Neurochem Res 49, 453–465 (2024). https://doi.org/10.1007/s11064-023-04052-1

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