Sortilin and L-type Calcium Channels May be Involved in the Unusual Mechanism of proBDNF Signaling in Regenerating Mouse Neuromuscular Junctions

Neurochemical Research. 2025. Vol. 50. Article 104.

Bogacheva P. O., Potapova D. A., A. E. Gaydukov

proBDNF and its main proteolytic product BDNF play crucial roles in maturation of neuromuscular junctions during development or reinnervation. We investigated the mechanisms of acute proBDNF effects on synaptic transmission in mouse motor synapses regenerating after nerve crush. The cleavage-resistant proBDNF mimicked the previously shown effect of cleavable proBDNF– GIRK-mediated decrease in the miniature endplate potential (MEPP) frequency accompanied by slight hyperpolarization of postsynaptic membrane. Remarkably, this effect did not utilize canonical proBDNF signaling pathway since inhibition of either p75 receptors with LM11A-31 or sortilin with AF38469 was not able to prevent it. Without sortilin activity, proBDNF downregulated the quantal content of multiquantal endplate potentials (EPP). This non-canonical action of proneurotrophin via TrkB receptors highlights the important role of sortilin as a safeguard preventing the spread of the negative effect of proBDNF on the evoked neurotransmitter release in regenerating motor synapses. In the absence of sortilin activity L-type calcium channels emerged as the key players providing proBDNF-induced decrease of EPP quantal content, while they were not involved in proBDNF-induced decrease of MEPP frequency. Sortilin-independent but TrkB- and GIRK-mediated inhibition of spontaneous release by proBDNF was not associated with the activity of acetylcholine (M2) or purinergic (A1 and P2Y13) metabotropic receptors. We propose that depending on sortilin involvement, proBDNF selectively affects spontaneous or evoked quantal neurotransmitter release via different branches of signaling pathway that ensure the presynaptic activation of GIRK or L-type calcium channels, respectively.

Keywords: regeneration, neuromuscular junction, L-type calcium channels, proBDNF, GIRK, Sortilin