Neurotransmitter Acetylcholine Negatively Regulates Neuromuscular Synapse Formation by a Cdk5-Dependent Mechanism

The Salk Institute, La Jolla, California 92037, USA.
Neuron (Impact Factor: 15.05). 06/2005; 46(4):569-79. DOI: 10.1016/j.neuron.2005.04.002
Source: PubMed


Synapse formation requires interactions between pre- and postsynaptic cells to establish the connection of a presynaptic nerve terminal with the neurotransmitter receptor-rich postsynaptic apparatus. At developing vertebrate neuromuscular junctions, acetylcholine receptor (AChR) clusters of nascent postsynaptic apparatus are not apposed by presynaptic nerve terminals. Two opposing activities subsequently promote the formation of synapses: positive signals stabilize the innervated AChR clusters, whereas negative signals disperse those that are not innervated. Although the nerve-derived protein agrin has been suggested to be a positive signal, the negative signals remain elusive. Here, we show that cyclin-dependent kinase 5 (Cdk5) is activated by ACh agonists and is required for the ACh agonist-induced dispersion of the AChR clusters that have not been stabilized by agrin. Genetic elimination of Cdk5 or blocking ACh production prevents the dispersion of AChR clusters in agrin mutants. Therefore, we propose that ACh negatively regulates neuromuscular synapse formation through a Cdk5-dependent mechanism.

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    • "In this regard, neural-and muscle-derived molecules have been described to play such inhibitory roles at the vertebrate NMJ. One the one hand, the neurotransmitter ACh displays an AChRdisaggregating activity at the most abundant non-innervated ( " extrasynaptic " ) domains of the muscle membrane at nascent NMJs (Lin et al., 2005; Misgeld et al., 2005). ACh acts through the cyclin-dependent kinase 5 (Cdk5) which phosphorylates the intermediate filament protein nestin, that becomes dissociated from the cytoskeletal network and is subsequently degraded (Fu et al., 2005; Yang et al., 2011). "
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    • "There is a careful balance between signals promoting and inhibiting postsynaptic stabilisation. A compromised presynaptic terminal may no longer provide enough positive signals, such as AGRN (McMahan, 1990; Misgeld et al. 2005), that stabilise the clustering of AChR at the postsynaptic side, to counteract a prolonged exposure to ACh, which is also a signal for AChR cluster dissipation (Lin et al. 2005; Misgeld et al. 2005). "
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    • "Muscle depolarization induced by released ACh is a negative signal for AChRs. It inhibits AChR localization, stability [62], and transcription along the muscle fiber by stimulation of cyclin-dependent kinase 5 [63, 64], protein kinase C (PKC), and Ca2+/calmodulin-dependent kinase II (CaMKII) [65]. Indeed, mutant mice lacking acetyltransferase, a biosynthetic enzyme for ACh, develop faster and larger AChR clusters; they also exhibit hyperinnervation due to a broader distribution of AChR clusters along the muscle fiber [66, 67]. "
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