Amplification of neuromuscular transmission by methylprednisolone involves activation of presynaptic facilitatory adenosine A2A receptors and redistribution of synaptic vesicles

Tetanic Facilitation of Neuromuscular Transmission by Adenosine A_2A and Muscarinic M₁ Receptors is Dependent on the Uptake of Choline via High-Affinity Transporters

“…The concurrent activation of facilitatory muscarinic M 1 autoreceptors may also play a role. However, in contrast to the findings by VeldsemaCurrie et al [51], pretreatment with HC-3 failed to modify methylprednisolone-induced tetanic facilitation of nerve-evoked [ 3 H]ACh release and muscle contractions (increase in R-value), thus indicating that interference with the HChT function plays a minor (if at all) role on neuromuscular transmission facilitation by the corticosteroid [33].…”

“…Facilitation of the neuromuscular transmission by methylprednisolone during high-frequency motor nerve activity coincides with the predominant adenosine A 2A receptor tonus, which coordinates the interplay with other receptors (e.g., muscarinic) on motor nerve endings to sustain ACh release that is required to overcome tetanic neuromuscular depression in myasthenics [31,32]. Recently, we showed that the amplification of neuromuscular transmission by methylprednisolone depends on the tonic activation of presynaptic facilitatory adenosine A 2A receptors secondary to endogenous adenosine generated from ATP released under resting conditions [33]. The concurrent activation of facilitatory muscarinic M 1 autoreceptors may also play a role.…”

“…Using video microscopy with the fluorescent FM4-64 dye and Dyngo-4a (a potent inhibitor of helical dynamin I) to monitor endocytosis [58], we showed that corticosteroids negatively modulate synaptic vesicle turnover, thereby increasing the release probability of immature recycled vesicles via a mechanism that involves activation of adenosine A 2A and muscarinic M 1 receptors leading to downstream phosphorylation of synapsin I by PKA [33]. This is in line with the theory that bulk endocytosis contributes to the maintenance of neuromuscular transmission by regenerating synaptic vesicles to the readily releasable pool during high-frequency stimulation trains [59].…”

“…Fluorescence decay was expressed as a percentage of maximal loading considering that 100% is the fluorescence intensity at zero time. As previously described, nerve-evoked FM4-64 intensity decay reflects synaptic vesicle exocytosis at the nerve terminal [33,[36][37][38][39]41]. hexatrienyl) pyridiniumdibromide (FM4-64) and α-bungarotoxin (α-BTX) were purchased from ThermoFisher Scientific (Waltham, MA, USA).…”

“…Interestingly, this situation can be restored by the exogenous application of the adenosine precursor AMP. Moreover, methylprednisolone, a corticosteroid that is widely used to depress immune responses in MG patients, also contributes to ameliorate motor deficits by promoting neuromuscular transmission through a mechanism that involves tonic activation of neuronal facilitatory adenosine A 2A receptors leading to increases in the release probability of immature recycled vesicles [33].…”