Time Lapse in Vivo Visualization of Developmental Stabilization of Synaptic Receptors at Neuromuscular Junctions

Yampolsky, Pessah; Pacifici, Pier Giorgio; Lomb, Lukas; Giese, Günter; Rudolf, Rüdiger; Röder, Ira V.; Witzemann, Veit

doi:10.1074/jbc.m110.168880

Cited by 18 publications

(23 citation statements)

References 32 publications

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“…Particularly, receptor recycling plays an important role in the activity-dependent regulation of AChR turnover (Akaaboune et al, 1999;Bruneau et al, 2005;Röder et al, 2008). To mediate efficient AChR recycling, the subsynaptic enrichment of a complex of AChR, myosin Va, and protein kinase A (PKA) type I was found to be essential (Röder et al, 2010;Rudolf et al, 2011;Yampolsky et al, 2010a). This fits with a longproposed function of PKA type I in AChR stabilisation (Nelson et al, 2003;Shyng et al, 1991;Xu and Salpeter, 1997), which is probably mediated by neurogenic factors, such as a-calcitonin gene-related peptide (Nelson et al, 2003).…”

Section: Introductionmentioning

confidence: 57%

“…Based on our findings and the general aspects of rapsyn and BiFC as just mentioned, we speculate that rapsyn interacts with PKA-RIa in a domain close to the NMJ. As shown recently, the accumulation of PKA-RIa in this region is crucial for proper AChR stabilisation (Röder et al, 2010;Röder et al, 2008;Yampolsky et al, 2010a).…”

Section: Rapsyn In Pka Anchoring and Nmj Plasticity 719mentioning

confidence: 99%

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Rapsyn mediates subsynaptic anchoring of PKA type I and stabilisation of acetylcholine receptor in vivo

Choi

Berrera

Reischl

et al. 2012

Journal of Cell Science

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SummaryThe stabilisation of acetylcholine receptors (AChRs) at the neuromuscular junction depends on muscle activity and the cooperative action of myosin Va and protein kinase A (PKA) type I. To execute its function, PKA has to be present in a subsynaptic microdomain where it is enriched by anchoring proteins. Here, we show that the AChR-associated protein, rapsyn, interacts with PKA type I in C2C12 and T-REx293 cells as well as in live mouse muscle beneath the neuromuscular junction. Molecular modelling, immunoprecipitation and bimolecular fluorescence complementation approaches identify an a-helical stretch of rapsyn to be crucial for binding to the dimerisation and docking domain of PKA type I. When expressed in live mouse muscle, a peptide encompassing the rapsyn a-helical sequence efficiently delocalises PKA type I from the neuromuscular junction. The same peptide, as well as a rapsyn construct lacking the a-helical domain, induces severe alteration of acetylcholine receptor turnover as well as fragmentation of synapses. This shows that rapsyn anchors PKA type I in close proximity to the postsynaptic membrane and suggests that this function is essential for synapse maintenance.

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Section: Introductionmentioning

confidence: 57%

Section: Rapsyn In Pka Anchoring and Nmj Plasticity 719mentioning

confidence: 99%

Rapsyn mediates subsynaptic anchoring of PKA type I and stabilisation of acetylcholine receptor in vivo

Choi

Berrera

Reischl

et al. 2012

Journal of Cell Science

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“…Even if muscle fibers are ablated, a low level of nAChRs persists for some time (Li and Thompson, 2011). Stabilization of nAChR clusters results from nAChR recycling, regulated by the motor nerve terminal and by skeletal muscle activity (Akaaboune et al, 1999; Yampolsky et al, 2010; Li and Thompson, 2011; Ouanounou et al, 2016). With motor nerve denervation and aging, nAChR clusters undergo marked morphological remodeling, with a high percentage of nAChR cluster fragmentation (Falk et al, 2015; Tintignac et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Morphological Regeneration and Functional Recovery of Neuromuscular Junctions after Tourniquet-Induced Injuries in Mouse Hindlimb

Zhang

Corrick

et al. 2017

Front. Physiol.

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Tourniquet application and its subsequent release cause serious injuries to the skeletal muscle, nerve, and neuromuscular junction (NMJ) due to mechanical compression and ischemia-reperfusion (IR). Monitoring structural and functional repair of the NMJ, nerve, and skeletal muscle after tourniquet-induced injuries is beneficial in exploring potential cellular and molecular mechanisms responsible for tourniquet-induced injuries, and for establishing effective therapeutic interventions. Here, we observed long-term morphological and functional changes of the NMJ in a murine model of tourniquet-induced hindlimb injuries. Unilateral hindlimbs of C57/BL6 mice were subjected to 3 h of tourniquet by placing an orthodontic rubber band, followed by varied periods of tourniquet release (1 day, 3 days, 1 week, 2 weeks, 4 weeks, and 6 weeks). NMJ morphology in the gastrocnemius muscle was imaged, and the endplate potential (EPP) was recorded to evaluate NMJ function. In NMJs, nicotinic acetylcholine receptor (nAChR) clusters normally displayed an intact, pretzel-like shape, and all nAChR clusters were innervated (100%) by motor nerve terminals. During 3 h of tourniquet application and varied periods of tourniquet release, NMJs in the gastrocnemius muscle were characterized by morphological and functional changes. At 1 day and 3 days of tourniquet release, nAChR clusters retained normal, pretzel-like shapes, whereas motor nerve terminals were completely destroyed and no EPPs recorded. From 1 to 6 weeks of tourniquet release, motor nerve terminals gradually regenerated, even reaching that seen in sham mice, whereas nAChR clusters were gradually fragmented with prolongation of tourniquet release. Additionally, the amplitude of EPPs gradually increased with prolongation of tourniquet release. However, even at 6 weeks after tourniquet release, the amplitude of EPPs did not restore to the level seen in sham mice (13.9 ± 1.1 mV, p < 0.05 vs. sham mice, 29.8 ± 1.0 mV). The data suggest that tourniquet application and subsequent release impair the structure and function of NMJs. Morphological change in motor nerve terminals is faster than in nAChR clusters in NMJs. Slow restoration of fragmented nAChR clusters possibly dampens neuromuscular transmission during the long phase following tourniquet release.

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“…A potential target for CaMKII at the NMJ could be myosin Va, which is crucial to recruit AChR-containing recycling carriers to the post-synaptic membrane (Röder et al, 2008; Yampolsky et al, 2010). Myosin V molecules are CaMKII-regulated motor proteins (Costa et al, 1999) and are also important for activity- and Ca 2+ -dependent recycling of AMPA receptors at central synapses (Correia et al, 2008; Wang et al, 2008).…”

Section: Molecular Characteristics and Biomarkers At Nmjmentioning

confidence: 99%

Degeneration of Neuromuscular Junction in Age and Dystrophy

Rudolf

Khan

Labeit

et al. 2014

Front. Aging Neurosci.

159

141

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Functional denervation is a hallmark of aging sarcopenia as well as of muscular dystrophy. It is thought to be a major factor reducing skeletal muscle mass, particularly in the case of sarcopenia. Neuromuscular junctions (NMJs) serve as the interface between the nervous and skeletal muscular systems, and thus they may receive pathophysiological input of both pre- and post-synaptic origin. Consequently, NMJs are good indicators of motor health on a systemic level. Indeed, upon sarcopenia and dystrophy, NMJs morphologically deteriorate and exhibit altered characteristics of primary signaling molecules, such as nicotinic acetylcholine receptor and agrin. Since a remarkable reversibility of these changes can be observed by exercise, there is significant interest in understanding the molecular mechanisms underlying synaptic deterioration upon aging and dystrophy and how synapses are reset by the aforementioned treatments. Here, we review the literature that describes the phenomena observed at the NMJ in sarcopenic and dystrophic muscle as well as to how these alterations can be reversed and to what extent. In a second part, the current information about molecular machineries underlying these processes is reported.

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Time Lapse in Vivo Visualization of Developmental Stabilization of Synaptic Receptors at Neuromuscular Junctions

Cited by 18 publications

References 32 publications

Rapsyn mediates subsynaptic anchoring of PKA type I and stabilisation of acetylcholine receptor in vivo

Rapsyn mediates subsynaptic anchoring of PKA type I and stabilisation of acetylcholine receptor in vivo

Morphological Regeneration and Functional Recovery of Neuromuscular Junctions after Tourniquet-Induced Injuries in Mouse Hindlimb

Degeneration of Neuromuscular Junction in Age and Dystrophy

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