scholarly journals Neuregulin/ErbB regulate neuromuscular junction development by phosphorylation of α-dystrobrevin

2011 ◽  
Vol 195 (7) ◽  
pp. 1171-1184 ◽  
Author(s):  
Nadine Schmidt ◽  
Mohammed Akaaboune ◽  
Nadesan Gajendran ◽  
Isabel Martinez-Pena y Valenzuela ◽  
Sarah Wakefield ◽  
...  
Keyword(s):  
Nervous System ◽  
Synaptic Transmission ◽  
Acetylcholine Receptors ◽  
Synapse Formation ◽  
Neuromuscular Synapse ◽  
Muscle Membrane ◽  
Erbb Signaling ◽  
Cultured Myotubes ◽  
The Stability ◽  
And Function

Neuregulin (NRG)/ErbB signaling is involved in numerous developmental processes in the nervous system, including synapse formation and function in the central nervous system. Although intensively investigated, its role at the neuromuscular synapse has remained elusive. Here, we demonstrate that loss of neuromuscular NRG/ErbB signaling destabilized anchoring of acetylcholine receptors (AChRs) in the postsynaptic muscle membrane and that this effect was caused by dephosphorylation of α-dystrobrevin1, a component of the postsynaptic scaffold. Specifically, in mice in which NRG signaling to muscle was genetically or pharmacologically abolished, postsynaptic AChRs moved rapidly from the synaptic to the perisynaptic membrane, and the subsynaptic scaffold that anchors the AChRs was impaired. These defects combined compromised synaptic transmission. We further show that blockade of NRG/ErbB signaling abolished tyrosine phosphorylation of α-dystrobrevin1, which reduced the stability of receptors in agrin-induced AChR clusters in cultured myotubes. Our data indicate that NRG/ErbB signaling maintains high efficacy of synaptic transmission by stabilizing the postsynaptic apparatus via phosphorylation of α-dystrobrevin1.

scholarly journals APP interacts with LRP4 and agrin to coordinate the development of the neuromuscular junction in mice

eLife ◽  
2013 ◽  
Vol 2 ◽  
Author(s):  
Hong Y Choi ◽  
Yun Liu ◽  
Christian Tennert ◽  
Yoshie Sugiura ◽  
Andromachi Karakatsani ◽  
...  
Keyword(s):  
Neuromuscular Junction ◽  
Molecular Mechanisms ◽  
Synapse Formation ◽  
Transmembrane Domain ◽  
Neuromuscular Synapse ◽  
Apoe Receptor ◽  
Cultured Myotubes ◽  
Perinatal Lethality ◽  
And Function ◽  
Achr Clustering

ApoE, ApoE receptors and APP cooperate in the pathogenesis of Alzheimer’s disease. Intriguingly, the ApoE receptor LRP4 and APP are also required for normal formation and function of the neuromuscular junction (NMJ). In this study, we show that APP interacts with LRP4, an obligate co-receptor for muscle-specific tyrosine kinase (MuSK). Agrin, a ligand for LRP4, also binds to APP and co-operatively enhances the interaction of APP with LRP4. In cultured myotubes, APP synergistically increases agrin-induced acetylcholine receptor (AChR) clustering. Deletion of the transmembrane domain of LRP4 (LRP4 ECD) results in growth retardation of the NMJ, and these defects are markedly enhanced in APP−/−;LRP4ECD/ECD mice. Double mutant NMJs are significantly reduced in size and number, resulting in perinatal lethality. Our findings reveal novel roles for APP in regulating neuromuscular synapse formation through hetero-oligomeric interaction with LRP4 and agrin and thereby provide new insights into the molecular mechanisms that govern NMJ formation and maintenance.

scholarly journals Cholinesterases in Tripartite Neuromuscular Synapse

2021 ◽  
Vol 14 ◽  
Author(s):  
Konstantin A. Petrov ◽  
Svetlana E. Proskurina ◽  
Eric Krejci
Keyword(s):  
Synaptic Transmission ◽  
Motor Neuron ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Neuromuscular Synapse ◽  
Genetic Studies ◽  
Pathological Conditions ◽  
Α7 Nicotinic Acetylcholine Receptors ◽  
Terminal Schwann Cells

The neuromuscular junction (NMJ) is a tripartite synapse in which not only presynaptic and post-synaptic cells participate in synaptic transmission, but also terminal Schwann cells (TSC). Acetylcholine (ACh) is the neurotransmitter that mediates the signal between the motor neuron and the muscle but also between the motor neuron and TSC. ACh action is terminated by acetylcholinesterase (AChE), anchored by collagen Q (ColQ) in the basal lamina of NMJs. AChE is also anchored by a proline-rich membrane anchor (PRiMA) to the surface of the nerve terminal. Butyrylcholinesterase (BChE), a second cholinesterase, is abundant on TSC and anchored by PRiMA to its plasma membrane. Genetic studies in mice have revealed different regulations of synaptic transmission that depend on ACh spillover. One of the strongest is a depression of ACh release that depends on the activation of α7 nicotinic acetylcholine receptors (nAChR). Partial AChE deficiency has been described in many pathologies or during treatment with cholinesterase inhibitors. In addition to changing the activation of muscle nAChR, AChE deficiency results in an ACh spillover that changes TSC signaling. In this mini-review, we will first briefly outline the organization of the NMJ. This will be followed by a look at the role of TSC in synaptic transmission. Finally, we will review the pathological conditions where there is evidence of decreased AChE activity.

scholarly journals Stabilization of Acetylcholine Receptors by Exogenous ATP and Its Reversal by cAMP and Calcium

1997 ◽  
Vol 138 (1) ◽  
pp. 159-165 ◽  
Author(s):  
James P. O'Malley ◽  
Charlotte T. Moore ◽  
Miriam M. Salpeter
Keyword(s):  
Neuromuscular Junction ◽  
Half Life ◽  
Acetylcholine Receptors ◽  
Muscle Cells ◽  
Muscle Membrane ◽  
Intracellular Camp ◽  
Signaling Systems ◽  
Camp Analogue ◽  
Degradation Rates ◽  
The Stability

Innervation of the neuromuscular junction (nmj) affects the stability of acetylcholine receptors (AChRs). A neural factor that could affect AChR stabilization was studied using cultured muscle cells since they express two distinct populations of AChRs similar to those seen at the nmjs of denervated muscle. These two AChR populations are (in a ratio of 9 to 1) a rapidly degrading population (Rr) with a degradation half-life of ∼1 d and a slowly degrading population (Rs) that can alternate between an accelerated form (half-life ∼3–5 d) and a stabilized form (half-life ∼10 d), depending upon the state of innervation of the muscle. Previous studies have shown that elevation of intracellular cAMP can stabilize the Rs, but not the Rr. We report here that in cultured rat muscle cells, exogenous ATP stabilized the degradation half-life of Rr and possibly also the Rs. Furthermore, pretreatment with ATP caused more stable AChRs to be inserted into the muscle membrane. Thus, in the presence of ATP, the degradation rates of the Rr and Rs overlap. This suggests that ATP released from the nerve may play an important role in the regulation of AChR degradation. Treatment with either the cAMP analogue dibutyryl-cAMP (dB-cAMP) or the calcium mobilizer ryanodine caused the ATP-stabilized Rr to accelerate back to a half-life of 1 d. Thus, at least three signaling systems (intracellular cAMP, Ca2+, and extracellular ATP) have the potential to interact with each other in the building of an adult neuromuscular junction.

scholarly journals Neuron–glia interactions: the roles of Schwann cells in neuromuscular synapse formation and function

2011 ◽  
Vol 31 (5) ◽  
pp. 295-302 ◽  
Author(s):  
Yoshie Sugiura ◽  
Weichun Lin
Keyword(s):  
Schwann Cells ◽  
Motor Neurons ◽  
Nerve Terminal ◽  
Synapse Formation ◽  
Neuromuscular Synapse ◽  
Synaptic Activity ◽  
Nerve Terminals ◽  
Presynaptic Nerve Terminal ◽  
Presynaptic Nerve Terminals ◽  
And Function

The NMJ (neuromuscular junction) serves as the ultimate output of the motor neurons. The NMJ is composed of a presynaptic nerve terminal, a postsynaptic muscle and perisynaptic glial cells. Emerging evidence has also demonstrated an existence of perisynaptic fibroblast-like cells at the NMJ. In this review, we discuss the importance of Schwann cells, the glial component of the NMJ, in the formation and function of the NMJ. During development, Schwann cells are closely associated with presynaptic nerve terminals and are required for the maintenance of the developing NMJ. After the establishment of the NMJ, Schwann cells actively modulate synaptic activity. Schwann cells also play critical roles in regeneration of the NMJ after nerve injury. Thus, Schwann cells are indispensable for formation and function of the NMJ. Further examination of the interplay among Schwann cells, the nerve and the muscle will provide insights into a better understanding of mechanisms underlying neuromuscular synapse formation and function.

scholarly journals Structure, Expression, and Function of ICAM-5

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Heping Yang
Keyword(s):  
Nervous System ◽  
Cell Adhesion ◽  
Adhesion Molecule ◽  
Synapse Formation ◽  
The Other ◽  
Intercellular Adhesion Molecule ◽  
Cellular Functions ◽  
Binding Partners ◽  
The Central Nervous System ◽  
And Function

Cell adhesion is of utmost importance in normal development and cellular functions. ICAM-5 (intercellular adhesion molecule-5, telencephalin, TLN) is a member of the ICAM family of adhesion proteins. As a novel cell adhesion molecule, ICAM-5 shares many structural similarities with the other members of IgSF, especially the ICAM subgroup; however, ICAM-5 has several unique properties compared to the other ICAMs. With its nine extracellular Ig domains, ICAM-5 is the largest member of ICAM subgroup identified so far. Therefore, it is much more complex than the other ICAMs. The expression of ICAM-5 is confined to the telencephalic neurons of the central nervous system whereas all the other ICAM members are expressed mostly by cells in the immune and blood systems. The developmental appearance of ICAM-5 parallels the time of dendritic elongation and branching, and synapse formation in the telencephalon. As a somatodendrite-specific adhesion molecule, ICAM-5 not only participates in immune-nervous system interactions, it could also participate in neuronal activity, Dendrites’ targeting signals, and cognition. It would not be surprising if future investigations reveal more binding partners and other related functions of ICAM-5.

scholarly journals Acetylated α-tubulin residue K394 regulates microtubule stability to shape the growth of axon terminals

2021 ◽  
Author(s):  
Harriet A. J. Saunders ◽  
Dena M. Johnson-Schlitz ◽  
Brian V. Jenkins ◽  
Peter J. Volkert ◽  
Sihui Z. Yang ◽  
...  
Keyword(s):  
Nervous System ◽  
Neuron Type ◽  
Dimer Interface ◽  
Tubulin Dimer ◽  
Over Expression ◽  
Axon Terminals ◽  
Microtubule Stability ◽  
The Stability ◽  
And Function ◽  
Conserved Residue

Microtubules are essential to neuron shape and function. Therefore, the stability of the microtubule cytoskeleton must be carefully regulated. Acetylation of tubulin has the potential to directly tune microtubule stability, and proteomic studies have identified several acetylation sites in α-tubulin. This includes the highly conserved residue lysine 394 (K394), which is located at the αβ-tubulin dimer interface. Using a fly model, we show that α-tubulin K394 is acetylated in the nervous system and is an essential residue. We found that an acetylation-blocking mutation in endogenous α-tubulin, K394R, perturbs the synaptic morphogenesis of motoneurons by reducing microtubule stability. Intriguingly, the K394R mutation has opposite effects on the growth of two functionally and morphologically distinct motoneurons, revealing neuron-type-specific responses when microtubule stability is altered. Eliminating the deacetylase HDAC6 increases K394 acetylation, and the over-expression of HDAC6 reduces microtubule stability similar to the K394 mutant. Thus, our findings implicate α-tubulin K394 and its acetylation in the regulation of microtubule stability and suggest that HDAC6 regulates K394 acetylation during synaptic morphogenesis.

scholarly journals Laminin-1 redistributes postsynaptic proteins and requires rapsyn, tyrosine phosphorylation, and Src and Fyn to stably cluster acetylcholine receptors

2002 ◽  
Vol 157 (5) ◽  
pp. 883-895 ◽  
Author(s):  
P. Angelo Marangi ◽  
Simon T. Wieland ◽  
Christian Fuhrer
Keyword(s):  
Tyrosine Phosphorylation ◽  
Tyrosine Kinases ◽  
Acetylcholine Receptors ◽  
Synapse Formation ◽  
Cluster Formation ◽  
Neuromuscular Synapse ◽  
Achr Cluster ◽  
Signaling Mechanisms ◽  
Neuromuscular Synaptogenesis ◽  
Laminin 1

Clustering of acetylcholine receptors (AChRs) is a critical step in neuromuscular synaptogenesis, and is induced by agrin and laminin which are thought to act through different signaling mechanisms. We addressed whether laminin redistributes postsynaptic proteins and requires key elements of the agrin signaling pathway to cause AChR aggregation. In myotubes, laminin-1 rearranged dystroglycans and syntrophins into a laminin-like network, whereas inducing AChR-containing clusters of dystrobrevin, utrophin, and, to a marginal degree, MuSK. Laminin-1 also caused extensive coclustering of rapsyn and phosphotyrosine with AChRs, but none of these clusters were observed in rapsyn −/− myotubes. In parallel with clustering, laminin-1 induced tyrosine phosphorylation of AChR β and δ subunits. Staurosporine and herbimycin, inhibitors of tyrosine kinases, prevented laminin-induced AChR phosphorylation and AChR and phosphotyrosine clustering, and caused rapid dispersal of clusters previously induced by laminin-1. Finally, laminin-1 caused normal aggregation of AChRs and phosphotyrosine in myotubes lacking both Src and Fyn kinases, but these clusters dispersed rapidly after laminin withdrawal. Thus, laminin-1 redistributes postsynaptic proteins and, like agrin, requires tyrosine kinases for AChR phosphorylation and clustering, and rapsyn for AChR cluster formation, whereas cluster stabilization depends on Src and Fyn. Therefore, the laminin and agrin signaling pathways overlap intracellularly, which may be important for neuromuscular synapse formation.

Effect of Dendroaspis neurotoxins on synaptic transmission in the spinal cord of the frog

1975 ◽  
Vol 190 (1099) ◽  
pp. 267-274 ◽  
Keyword(s):  
Spinal Cord ◽  
Central Nervous System ◽  
Nervous System ◽  
Synaptic Transmission ◽  
Acetylcholine Receptors ◽  
Neuromuscular Transmission ◽  
Presynaptic Action ◽  
Cholinergic Pathway ◽  
The Central Nervous System

Six neurotoxins from Dendroaspis venom, and α -bungarotoxin, were tested on a cholinergic synaptic pathway in the isolated spinal cord of the frog. Four dendrotoxins, which block neuromuscular transmission, also blocked the cholinergic pathway in the spinal cord. In both cases the block is slowly reversible and not due to presynaptic action. The dendrotoxins appear to act by blocking acetylcholine receptors and are therefore potentially useful for the localization and isolation of acetylcholine receptors in the central nervous system of vertebrates.

scholarly journals PTPσ functions as a presynaptic receptor for the glypican-4/LRRTM4 complex and is essential for excitatory synaptic transmission

2015 ◽  
Vol 112 (6) ◽  
pp. 1874-1879 ◽  
Author(s):  
Ji Seung Ko ◽  
Gopal Pramanik ◽  
Ji Won Um ◽  
Ji Seon Shim ◽  
Dongmin Lee ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Synapse Formation ◽  
Transmembrane Protein ◽  
Protein Tyrosine Phosphatases ◽  
Excitatory Synaptic Transmission ◽  
Receptor Protein ◽  
Synapse Development ◽  
Dependent Manner ◽  
And Function ◽  
Receptor Protein Tyrosine Phosphatases

Leukocyte common antigen-related receptor protein tyrosine phosphatases—comprising LAR, PTPδ, and PTPσ—are synaptic adhesion molecules that organize synapse development. Here, we identify glypican 4 (GPC-4) as a ligand for PTPσ. GPC-4 showed strong (nanomolar) affinity and heparan sulfate (HS)-dependent interaction with the Ig domains of PTPσ. PTPσ bound only to proteolytically cleaved GPC-4 and formed additional complex with leucine-rich repeat transmembrane protein 4 (LRRTM4) in rat brains. Moreover, single knockdown (KD) of PTPσ, but not LAR, in cultured neurons significantly reduced the synaptogenic activity of LRRTM4, a postsynaptic ligand of GPC-4, in heterologous synapse-formation assays. Finally, PTPσ KD dramatically decreased both the frequency and amplitude of excitatory synaptic transmission. This effect was reversed by wild-type PTPσ, but not by a HS-binding–defective PTPσ mutant. Our results collectively suggest that presynaptic PTPσ, together with GPC-4, acts in a HS-dependent manner to maintain excitatory synapse development and function.

Sign in / Sign up

Export Citation Format

Share Document