scholarly journals Regulatory Function of Sympathetic Innervation on the Endo/Lysosomal Trafficking of Acetylcholine Receptor

2021 ◽  
Vol 12 ◽  
Author(s):  
Tatjana Straka ◽  
Charlotte Schröder ◽  
Andreas Roos ◽  
Laxmikanth Kollipara ◽  
Albert Sickmann ◽  
...  
Keyword(s):  
Neuromuscular Junction ◽  
Acetylcholine Receptor ◽  
Ribosomal Proteins ◽  
Neuromuscular Junctions ◽  
Sympathetic Neurons ◽  
Sympathetic Innervation ◽  
Regulatory Function ◽  
Hindlimb Muscles ◽  
Nerve Muscle

Recent studies have demonstrated that neuromuscular junctions are co-innervated by sympathetic neurons. This co-innervation has been shown to be crucial for neuromuscular junction morphology and functional maintenance. To improve our understanding of how sympathetic innervation affects nerve–muscle synapse homeostasis, we here used in vivo imaging, proteomic, biochemical, and microscopic approaches to compare normal and sympathectomized mouse hindlimb muscles. Live confocal microscopy revealed reduced fiber diameters, enhanced acetylcholine receptor turnover, and increased amounts of endo/lysosomal acetylcholine-receptor-bearing vesicles. Proteomics analysis of sympathectomized skeletal muscles showed that besides massive changes in mitochondrial, sarcomeric, and ribosomal proteins, the relative abundance of vesicular trafficking markers was affected by sympathectomy. Immunofluorescence and Western blot approaches corroborated these findings and, in addition, suggested local upregulation and enrichment of endo/lysosomal progression and autophagy markers, Rab 7 and p62, at the sarcomeric regions of muscle fibers and neuromuscular junctions. In summary, these data give novel insights into the relevance of sympathetic innervation for the homeostasis of muscle and neuromuscular junctions. They are consistent with an upregulation of endocytic and autophagic trafficking at the whole muscle level and at the neuromuscular junction.

scholarly journals The Dystroglycan Complex Is Necessary for Stabilization of Acetylcholine Receptor Clusters at Neuromuscular Junctions and Formation of the Synaptic Basement Membrane

2001 ◽  
Vol 152 (3) ◽  
pp. 435-450 ◽  
Author(s):  
Christian Jacobson ◽  
Patrice D. Côté ◽  
Susana G. Rossi ◽  
Richard L. Rotundo ◽  
Salvatore Carbonetto
Keyword(s):  
Stem Cells ◽  
Basement Membrane ◽  
Acetylcholine Receptor ◽  
Neuromuscular Junctions ◽  
Embryonic Stem ◽  
Muscular Dystrophies ◽  
Chimeric Mice ◽  
Nerve Muscle ◽  
Receptor Clusters

The dystrophin-associated protein (DAP) complex spans the sarcolemmal membrane linking the cytoskeleton to the basement membrane surrounding each myofiber. Defects in the DAP complex have been linked previously to a variety of muscular dystrophies. Other evidence points to a role for the DAP complex in formation of nerve–muscle synapses. We show that myotubes differentiated from dystroglycan−/− embryonic stem cells are responsive to agrin, but produce acetylcholine receptor (AChR) clusters which are two to three times larger in area, about half as dense, and significantly less stable than those on dystroglycan+/+ myotubes. AChRs at neuromuscular junctions are similarly affected in dystroglycan-deficient chimeric mice and there is a coordinate increase in nerve terminal size at these junctions. In culture and in vivo the absence of dystroglycan disrupts the localization to AChR clusters of laminin, perlecan, and acetylcholinesterase (AChE), but not rapsyn or agrin. Treatment of myotubes in culture with laminin induces AChR clusters on dystroglycan+/+, but not −/− myotubes. These results suggest that dystroglycan is essential for the assembly of a synaptic basement membrane, most notably by localizing AChE through its binding to perlecan. In addition, they suggest that dystroglycan functions in the organization and stabilization of AChR clusters, which appear to be mediated through its binding of laminin.

Rapid and Reversible Effects of Activity on Acetylcholine Receptor Density at the Neuromuscular Junction in Vivo

Science ◽  
1999 ◽  
Vol 286 (5439) ◽  
pp. 503-507 ◽  
Author(s):  
Mohammed Akaaboune ◽  
Susan M. Culican ◽  
Stephen G. Turney ◽  
Jeff W. Lichtman
Keyword(s):  
Neuromuscular Junction ◽  
Acetylcholine Receptor ◽  
Half Life ◽  
Neuromuscular Junctions ◽  
Adult Mice ◽  
The Central Nervous System ◽  
Quantitative Fluorescence ◽  
Living Adult ◽  
Acetylcholine Receptor Density

Quantitative fluorescence imaging was used to study the regulation of acetylcholine receptor (AChR) number and density at neuromuscular junctions in living adult mice. At fully functional synapses, AChRs have a half-life of about 14 days. However, 2 hours after neurotransmission was blocked, the half-life of the AChRs was now less than a day; the rate was 25 times faster than before. Most of the lost receptors were not quickly replaced. Direct muscle stimulation or restoration of synaptic transmission inhibited this process. AChRs that were removed from nonfunctional synapses resided for hours in the perijunctional membrane before being locally internalized. Dispersed AChRs could also reaggregate at the junction once neurotransmission was restored. The rapid and reversible alterations in AChR density at the neuromuscular junction in vivo parallel changes thought to occur in the central nervous system at synapses undergoing potentiation and depression.

scholarly journals Dystroglycan Overexpression in Vivo Alters Acetylcholine Receptor Aggregation at the Neuromuscular Junction

2000 ◽  
Vol 227 (2) ◽  
pp. 595-605 ◽  
Author(s):  
R.David Heathcote ◽  
Jonathan M Ekman ◽  
Kevin P Campbell ◽  
Earl W Godfrey
Keyword(s):  
Neuromuscular Junction ◽  
Acetylcholine Receptor ◽  
Receptor Aggregation

scholarly journals Organization of β-adrenoceptor signaling compartments by sympathetic innervation of cardiac myocytes

2007 ◽  
Vol 176 (4) ◽  
pp. 521-533 ◽  
Author(s):  
Olga G. Shcherbakova ◽  
Carl M. Hurt ◽  
Yang Xiang ◽  
Mark L. Dell'Acqua ◽  
Qi Zhang ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Cardiac Myocytes ◽  
Contractile Function ◽  
Sympathetic Neurons ◽  
Sympathetic Innervation ◽  
Cardiac Contractile Function ◽  
Cardiac Contractile ◽  
Specific Regulation

The sympathetic nervous system regulates cardiac function through the activation of adrenergic receptors (ARs). β1 and β2ARs are the primary sympathetic receptors in the heart and play different roles in regulating cardiac contractile function and remodeling in response to injury. In this study, we examine the targeting and trafficking of β1 and β2ARs at cardiac sympathetic synapses in vitro. Sympathetic neurons form functional synapses with neonatal cardiac myocytes in culture. The myocyte membrane develops into specialized zones that surround contacting axons and contain accumulations of the scaffold proteins SAP97 and AKAP79/150 but are deficient in caveolin-3. The β1ARs are enriched within these zones, whereas β2ARs are excluded from them after stimulation of neuronal activity. The results indicate that specialized signaling domains are organized in cardiac myocytes at sites of contact with sympathetic neurons and that these domains are likely to play a role in the subtype-specific regulation of cardiac function by β1 and β2ARs in vivo.

scholarly journals Sympathetic innervation controls homeostasis of neuromuscular junctions in health and disease

2016 ◽  
Vol 113 (3) ◽  
pp. 746-750 ◽  
Author(s):  
Muzamil Majid Khan ◽  
Danilo Lustrino ◽  
Willian A. Silveira ◽  
Franziska Wild ◽  
Tatjana Straka ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Motor Neurons ◽  
Neuromuscular Junctions ◽  
Close Contact ◽  
Sympathetic Neurons ◽  
Sympathetic Innervation ◽  
Peroxisome Proliferator ◽  
Direct Stimulation ◽  
Peroxisome Proliferator Activated Receptor ◽  
And Function

The distribution and function of sympathetic innervation in skeletal muscle have largely remained elusive. Here we demonstrate that sympathetic neurons make close contact with neuromuscular junctions and form a network in skeletal muscle that may functionally couple different targets including blood vessels, motor neurons, and muscle fibers. Direct stimulation of sympathetic neurons led to activation of muscle postsynaptic β2-adrenoreceptor (ADRB2), cAMP production, and import of the transcriptional coactivator peroxisome proliferator-activated receptor γ-coactivator 1α (PPARGC1A) into myonuclei. Electrophysiological and morphological deficits of neuromuscular junctions upon sympathectomy and in myasthenic mice were rescued by sympathicomimetic treatment. In conclusion, this study identifies the neuromuscular junction as a target of the sympathetic nervous system and shows that sympathetic input is crucial for synapse maintenance and function.

scholarly journals Targeting of the ETS Factor Gabpα Disrupts Neuromuscular Junction Synaptic Function

2007 ◽  
Vol 27 (9) ◽  
pp. 3470-3480 ◽  
Author(s):  
Debra A. O'Leary ◽  
Peter G. Noakes ◽  
Nick A. Lavidis ◽  
Ismail Kola ◽  
Paul J. Hertzog ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Transcription Factor ◽  
Neuromuscular Junction ◽  
Acetylcholine Receptor ◽  
Neuromuscular Junctions ◽  
Binding Protein ◽  
Synaptic Function ◽  
Single Point Mutation ◽  
Structural Formation ◽  
Ga Binding Protein

ABSTRACT The GA-binding protein (GABP) transcription factor has been shown in vitro to regulate the expression of the neuromuscular proteins utrophin, acetylcholine esterase, and acetylcholine receptor subunits δ and ε through the N-box promoter motif (5′-CCGGAA-3′), but its in vivo function remains unknown. A single point mutation within the N-box of the gene encoding the acetylcholine receptor ε subunit has been identified in several patients suffering from postsynaptic congenital myasthenic syndrome, implicating the GA-binding protein in neuromuscular function and disease. Since conventional gene targeting results in an embryonic-lethal phenotype, we used conditional targeting to investigate the role of GABPα in neuromuscular junction and skeletal muscle development. The diaphragm and soleus muscles from mutant mice display alterations in morphology and distribution of acetylcholine receptor clusters at the neuromuscular junction and neurotransmission properties consistent with reduced receptor function. Furthermore, we confirmed decreased expression of the acetylcholine receptor ε subunit and increased expression of the γ subunit in skeletal muscle tissues. Therefore, the GABP transcription factor aids in the structural formation and function of neuromuscular junctions by regulating the expression of postsynaptic genes.

scholarly journals DEVELOPMENT OF THE NEUROMUSCULAR JUNCTION

1970 ◽  
Vol 47 (2) ◽  
pp. 423-436 ◽  
Author(s):  
Thomas L. Lentz
Keyword(s):  
Neuromuscular Junction ◽  
Synaptic Vesicles ◽  
Neuromuscular Junctions ◽  
Morphological Changes ◽  
Muscle Fibers ◽  
Lead Nitrate ◽  
Synaptic Function ◽  
Axon Termination ◽  
Nerve Muscle ◽  
Thiolacetic Acid

Following amputation of the limb of the newt, Triturus viridescens, muscle fibers dedifferentiate giving rise to mesenchymal cells. The earliest changes detected in neuromuscular junctions of dedifferentiating muscle fibers are the appearance of a few vacuoles and decrease in density of the terminal axoplasm. Later, synaptic vesicles become tightly clustered in the axon termination, and their content appears denser than normal. Then, vesicles diminish in number until few are seen in the ending. While these changes are occurring, the area of contact of nerve with muscle becomes smaller. Junctional folds persist only where the nerve maintains contact with muscle, but these are shorter than normal and appear as slight ridges on the muscle surface. Subsequently, the nerve withdraws from the muscle cell and is completely invested by Schwann cell cytoplasm, and all traces of junctional folds are lost at the former region of contact. Cholinesterase activity was localized with the thiolacetic acid-lead nitrate method. Even before marked morphological changes occur in the junction, DFP- and physostigmine-sensitive activity in the cleft between nerve and muscle is decreased in intensity. Activity continues to decrease as the area of nerve-muscle contact diminishes and junctional folds disappear. When the nerve has withdrawn from the muscle surface, only a few small deposits of lead are left in the intervening region. These results show that as muscle becomes less specialized during dedifferentiation, the neuromuscular junction also loses the cytological and cytochemical specializations associated with synaptic function.

scholarly journals The mechanism of agrin-induced acetylcholine receptor aggregation

1991 ◽  
Vol 331 (1261) ◽  
pp. 273-280 ◽  
Keyword(s):  
Neuromuscular Junction ◽  
Tyrosine Phosphorylation ◽  
Acetylcholine Receptor ◽  
Acetylcholine Receptors ◽  
Neuromuscular Junctions ◽  
Electric Organ ◽  
Motor Axon ◽  
Β Subunit ◽  
Axon Terminals ◽  
Receptor Aggregation

Agrin, a protein isolated from the synapse-rich electric organ of Torpedo californica , induces the formation of specializations on myotubes in culture which resemble the post-synaptic apparatus at the vertebrate skeletal neuromuscular junction. For example, the specializations contain aggregates of acetylcholine receptors and acetylcholinesterase. This report summarizes the evidence that the formation of the postsynaptic apparatus at developing and regenerating neuromuscular junctions is triggered by the release of agrin from motor axon terminals and describes results of recent experiments which suggest that agrininduced tyrosine phosphorylation of the β subunit of the acetylcholine receptor may play a role in receptor aggregation.

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