Purinergic Tuning of the Tripartite Neuromuscular Synapse

The vertebrate neuromuscular junction (NMJ) is a specialised chemical synapse involved in the transmission of bioelectric signals between a motor neuron and a skeletal muscle fiber, leading to muscle contraction. Typically, the NMJ is a tripartite synapse comprising (a) a presynaptic region represented by the motor nerve ending, (b) a postsynaptic skeletal motor endplate area, and (c) perisynaptic Schwann cells (PSCs) that shield the motor nerve terminal. Increasing evidence points towards the role of PSCs in the maintenance and control of neuromuscular integrity, transmission, and plasticity. Acetylcholine (ACh) is the main neurotransmitter at the vertebrate skeletal NMJ, and its role is fine-tuned by co-released purinergic neuromodulators, like adenosine 5 '-triphosphate (ATP) and its metabolite adenosine (ADO). Adenine nucleotides modulate transmitter release and expression of postsynaptic ACh receptors at motor synapses via the activation of P2Y and P2X receptors. Endogenously generated ADO modulates ACh release by acting via co-localised inhibitory A(1) and facilitatory A(2A) receptors on motor nerve terminals, whose tonic activation depends on the neuronal firing pattern and their interplay with cholinergic receptors and neuropeptides. Thus, the concerted action of adenine nucleotides, ADO, and ACh/neuropeptide co-transmitters is paramount to adapting the neuromuscular transmission to the working load under pathological conditions, like Myasthenia gravis. Unravelling these functional complexities prompted us to review our knowledge about the way purines orchestrate neuromuscular transmission and plasticity in light of the tripartite synapse concept, emphasising the often-forgotten role of PSCs in this context.

Automated summary

The vertebrate neuromuscular junction is a specialised synapse composed of a presynaptic region, a postsynaptic skeletal motor endplate area, and perisynaptic Schwann cells that play a significant role in maintaining neuromuscular integrity, transmission, and plasticity. Acetylcholine is the main neurotransmitter at this synapse and is modulated by purinergic neuromodulators. Adenine nucleotides and adenosine, released alongside acetylcholine, regulate transmitter release and expression of ACh receptors via P2Y and P2X receptors. Adenosine, through A1 and A2A receptors, also modulates ACh release by motor nerve terminals. Understanding the complex interplay between purines and neuromuscular transmission is essential for conditions like Myasthenia gravis.