Purinergic Tuning of the Tripartite Neuromuscular Synapse

Abstract

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 A1 and facilitatory A2A 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.

Presynaptic Purinergic Modulation of the Rat Neuro-Muscular Transmission

“…As is known, neuromodulation by adenine nucleotides occurs either directly, through the activation of ionotropic P2X/metabotropic P2Y receptors [6,7], or indirectly, after their extracellular breakdown to adenosine and subsequent activation of P1 receptors, which include four different subtypes (A 1 , A 2A , A 2B , and A 3 ) [15]. Nerve endings, skeletal muscle fibers, and Schwann cells express different subtypes of these purine receptors [16][17][18].…”

“…The final metabolite of ATP, adenosine, acts through A 1 , A 2A , A 2B , or A 3 receptors. In rodents, A 1 and A 2A receptors show high affinity for adenosine, while A 2B and A 3 are low affinity receptors [15]. The A 1 and A 3 receptors are associated with the G i/o protein, while the A 2A and A 2B are preferably associated with the G s protein.…”

“…Interestingly, in the frog myoneural junction, A 1 activation inhibits ACh release through a Ca 2+ -independent mechanism, which suggests direct interference with proteins involved in vesicular exocytosis [23]. A decrease in A 2A receptor function seems to be a hallmark of aging and some neuromuscular disorders [15].…”

“…Summing up, in this paper we demonstrated that the two purinergic pathways for modulating the induced ACh exocytosis skillfully complement each other (see Figure 8). It is known that the inhibitory effect of ATP in the synaptic cleft is more often observed at low frequencies of neuronal stimulation (≤1 Hz) [15]. This suggests that it is adenosine that, by activating both presynaptic inhibitory A 1 and facilitating A 2A receptors, depending on the paradigm of the situation, leads the adjusting effects of purines [39,40].…”