Activation of P2Y2 Receptors Promotes Neuromuscular Junction Formation during Muscle Reinnervation

Extracellular adenosine 5′-triphosphate (ATP), as neurotransmitter, is known to be an activity-dependent signaling molecule that regulates synaptic signaling. It is known to be co-released with acetylcholine from synaptic vesicle. The P2Y2 receptor (P2Y2R) is present in gastrocnemius muscles and co-localizes with post-synaptic acetylcholine receptors (AChRs). Accumulating evidence indicates that P2Y2R plays crucial roles in assembling neuromuscular junctions (NMJs), a peripheral synapse characterized by the clustering of AChRs on post-synaptic densities. This study investigated the alterations in P2Y2R expression during muscle reinnervation and the effect on NMJ formation. We found that P2Y2R consistently co-localized with AChR and sustained high expression in post-synaptic regions during muscle reinnervation. Notably, PSB1114-dependent stimulation of P2Y2R promoted NMJ formation and muscle reinnervation. The stimulatory effect of PSB1114 was significantly blocked by administration of the P2Y2R antagonist suramin. This study revealed distinctive patterns of expression and localization and a potential role of P2Y2R in promoting NMJ formation and regeneration during skeletal muscle reinnervation.