Synchronization of evoked secretion of quanta of mediator as a mechanism facilitating the action of sympathomimetics

Abstract

Experiments on frog neuromuscular junction preparations with extracellular recording of nerve terminal action potentials and single-quantum end-plate currents (EPC) were used to assess the time course of evoked quantum secretion of mediator by analyzing histograms of the distribution of true synaptic delays. These studies showed that noradrenaline, isoproterenol, and dobutamine change the kinetics of secretion of quanta, leading to synchronization of the process of mediator release; substances blocking beta-adrenoceptors (atenolol, propranolol) blocked this effect. Clonidine and phenylephrine, which activate alpha-receptors, had no effect on the kinetics of secretion, while the alpha-blocker phentolamine had no effect on the synchronizing action of noradrenaline. Reconstruction of multiquantum EPC from changes in the level of synchronization in the release of individual quanta, showed that EPC amplitude increased in response to noradrenaline by 17%, and that this was due only to alterations in the time course of secretion. These data led to the conclusion that there is a special presynaptic mechanism which facilitates the action of sympathomimetics, acting via beta-adrenoceptors.

Sympathetic innervation in skeletal muscle and its role at the neuromuscular junction

“…Furthermore, pharmacological stimulation of adrenoceptors in mouse diaphragm muscles affected spontaneous and evoked release of acetylcholine in an adrenoceptor-dependent manner: while agonists of adrenoceptors α 1 and β 1 decreased spontaneous release and quantal content, β 2 -AR stimulation increased quantal content (Tsentsevitsky et al 2020 ). Finally, norepinephrine and β 1 -agonists were found to synchronize evoked potentials in fatigued frog cutaneous pectoris and mouse diaphragm preparations (Bukharaeva et al 2000 ; Tsentsevitsky et al 2020 ). At difference, norepinephrine was not active in mouse soleus muscle, but epinephrine was (Khuzakhmetova and Bukharaeva 2021 ).…”

Adrenoceptors Modulate Cholinergic Synaptic Transmission at the Neuromuscular Junction

“…The asynchrony of individual quanta secretion is manifested by the dispersion of real synaptic delays of uni-quantal EPPs recorded in low Ca 2+ /high Mg 2+ conditions [ 52 , 55 ] or by a greater increase in the rise time of multi-quantal EPP compared to the MEPP rise time [ 56 , 57 ]. More synchronous release of quanta leads to the EPP amplitude increasing and thus facilitates synaptic transmission [ 58 ] ( Figure 1 ).…”

“…It was shown that the synchronizing action of noradrenaline leads to an increase in the amplitude of the multiquantal current of the end plate in the “fatigued” muscle and underlies the Orbeli–Ginetsinsky phenomenon—an increase in muscle contractions upon stimulation of the sympathetic nerve [ 6 , 7 ]. Therefore, the synchronization of ACh secretion may be a mechanism for the facilitating action of the sympathomimetics [ 58 ].…”