Extracellular ATP in activity‐dependent remodeling of the neuromuscular junction

Abstract

Electrical activity during early development affects the development and maintenance of synapses (Spitzer [2006]: Nature 4447:707-712), but the intercellular signals regulating maintenance of synapses are not well identified. At the neuromuscular junction, adenosine 5-triphosphate (ATP) is coreleased with acetylcholine at activated nerve terminals to modulate synaptic function. Here we use cocultured mouse motor neurons and muscle cells in a three-compartment cell culture chamber to test whether endogenously released ATP plays a role in activity-dependent maintenance of neuromuscular synapses. The results suggest that ATP release at the synapse counters the negative effect of electrical activity, thus stabilizing activated synapses. Confirming our previous work (Li et al. [2001]: Nat Neurosci 4:871-872), we found that in doubly innervated muscles, electrical stimulation induced heterosynaptic downregulation of the nonstimulated convergent input to the muscle fiber with no or little change of the stimulated inputs. However, in preparations that were stimulated in the presence of apyrase, an enzyme that degrades extracellular ATP, synapse downregulation of stimulated inputs was substantial and significant, and end plate potentials were reduced. Apyrase treatment for 20 h in the absence of stimulation did result in moderate diminution, but this was prevented by blocking spontaneous neural activity with tetrodotoxin. The P2 receptor blocker, suramin, also induced activity-dependent synapse diminution. The decrease in synaptic efficacy produced by prolonged stimulation in the presence of apyrase persisted for greater than 20 h, consistent with a developmental time-course and distinct from the rapid neuromodulatory actions of ATP that have been demonstrated by others. We conclude that extracellular ATP promotes stabilization of the neuromuscular junction and may play a role in activity-dependent synaptic modification during development.

Low‐dose suramin in autism spectrum disorder: a small, phase I/II, randomized clinical trial

“…Concentrations of eATP in the blood are another 500 times lower (10–20 nmol/L) 26. Purinergic effectors like ATP are also coreleased with canonical neurotransmitters like glutamate, dopamine, and serotonin during depolarization at every synapse in which they have been studied23 and play key roles in activity‐dependent synaptic remodeling 27. These and other features28, 29, 30 led us to test the hypothesis that the CDR8 was maintained by purinergic signaling 12, 13, 14…”

Electrical Stimuli Are Anti-Apoptotic in Skeletal Muscle via Extracellular ATP. Alteration of This Signal in Mdx Mice Is a Likely Cause of Dystrophy

“…ATP has been described as a regulator of inflammation, in embryonic and stem cell development, in ischemia and in several other processes [5] – [6] . In skeletal muscle, ATP has been implicated in the regulation of proliferation, differentiation and regeneration [7] – [8] and also in promoting the stabilization of the neuromuscular junction [9] . We have described that ATP is released trough Pannexin-1 (Panx1) channels by muscle cells after electrical stimulation and plays a crucial role in the activation of signaling pathways that lead to transcription of several genes [10] – [11] .…”

Peripheral Nervous System

“…These changes in neuromuscular junction structure were associated with muscle fibre atrophy and increases in the proportion of fast type muscle fibres. From an experimental study, it was concluded that extracellular ATP promotes stabilisation of the neuromuscular junction and may play a role in activity-dependent synaptic modifications during development (Jia et al 2007). From a study of sensory fibres, originating in the dorsal root ganglia (DRG) supplying skeletal muscle, it was concluded that P2X 5 and/or P2X 4 receptors in combination with proton-activated channels (ASIC) and TRPV1 channels are used to detect metabolites produced by contracting muscles, protons, ATP and lactate (Light et al 2008).…”