scholarly journals The HSPG Syndecan is a core organizer of cholinergic synapses in C. elegans

2020 ◽  
Author(s):  
Xin Zhou ◽  
Camille Vachon ◽  
Mélissa Cizeron ◽  
Océane Romatif ◽  
Hannes E. Bülow ◽  
...  
Keyword(s):  
Acetylcholine Receptors ◽  
Neuromuscular Junctions ◽  
Cholinergic Synapse ◽  
C Elegans ◽  
Synaptic Functions ◽  
Cholinergic Synapses ◽  
Synaptic Formation ◽  
Physical Interactions ◽  
Chemical Synapses ◽  
The Brain

SUMMARYThe extracellular matrix has emerged as an active component of chemical synapses regulating synaptic formation, maintenance and homeostasis. The heparan sulfate proteoglycan syndecans are known to regulate cellular and axonal migration in the brain. They are also enriched at synapses, but their synaptic functions remain more elusive. Here we show that SDN-1, the sole ortholog of syndecan in C. elegans, is absolutely required for the synaptic clustering of homomeric α7-like N-acetylcholine receptors (AChR) and regulates the synaptic content of heteromeric L-AChRs. SDN-1 is concentrated at neuromuscular junctions (NMJs) by the neurally-secreted synaptic organizer Ce-Punctin/MADD-4, which also activates the transmembrane netrin receptor DCC. Those cooperatively recruit the FARP and CASK orthologues that localize N-AChRs at cholinergic NMJs through physical interactions. Therefore, SDN-1 stands at the core of the cholinergic synapse organization by bridging the extracellular synaptic determinants to the intracellular synaptic scaffold that controls the postsynaptic receptor content.

Nicotinic Acetylcholine Receptors

2018 ◽  
Author(s):  
Roger L. Papke
Keyword(s):  
Ion Channels ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Neuromuscular Junctions ◽  
Cognitive Disorders ◽  
The Body ◽  
Nicotinic Acetylcholine ◽  
Synaptic Receptors ◽  
The Central Nervous System ◽  
The Brain

Acetylcholine, exquisitely evolved as a neurotransmitter, is made and released by the neurons that take the integrated output of the central nervous system throughout the body. At both neuromuscular junctions and autonomic ganglia, acetylcholine activates synaptic ion channels that take their name from the plant alkaloid nicotine, which is a mimic of the natural neurotransmitter. This chapter begins with the scientific discoveries related to the nicotinic acetylcholine receptors (nAChR) of the neuromuscular junction and how resulting insights led to an understanding of the fundamentals of synaptic transmission. The nAChR are one member of a superfamily of ligand-gated ion channels, and although in the brain excitatory neurotransmission is mediated by another family of synaptic receptors that are gated by glutamate, nicotinic receptors are important modulators of brain function and significant targets for drug development. In the brain, nAChR are targets for cognitive disorders and, tragically, responsible for tobacco addiction.

scholarly journals Constructing and Tuning Excitatory Cholinergic Synapses: The Multifaceted Functions of Nicotinic Acetylcholine Receptors in Drosophila Neural Development and Physiology

2021 ◽  
Vol 15 ◽  
Author(s):  
Justin S. Rosenthal ◽  
Quan Yuan
Keyword(s):  
Nervous System ◽  
Nicotinic Acetylcholine Receptors ◽  
Neural Development ◽  
Acetylcholine Receptors ◽  
Animal Studies ◽  
Neuromuscular Junctions ◽  
Nicotinic Acetylcholine ◽  
Molecular Features ◽  
Cholinergic Synapses

Nicotinic acetylcholine receptors (nAchRs) are widely distributed within the nervous system across most animal species. Besides their well-established roles in mammalian neuromuscular junctions, studies using invertebrate models have also proven fruitful in revealing the function of nAchRs in the central nervous system. During the earlier years, both in vitro and animal studies had helped clarify the basic molecular features of the members of the Drosophila nAchR gene family and illustrated their utility as targets for insecticides. Later, increasingly sophisticated techniques have illuminated how nAchRs mediate excitatory neurotransmission in the Drosophila brain and play an integral part in neural development and synaptic plasticity, as well as cognitive processes such as learning and memory. This review is intended to provide an updated survey of Drosophila nAchR subunits, focusing on their molecular diversity and unique contributions to physiology and plasticity of the fly neural circuitry. We will also highlight promising new avenues for nAchR research that will likely contribute to better understanding of central cholinergic neurotransmission in both Drosophila and other organisms.

scholarly journals A Novel and Functionally Diverse Class of Acetylcholine-gated Ion Channels

2021 ◽  
Author(s):  
Iris Hardege ◽  
Julia Morud ◽  
William R Schafer
Keyword(s):  
Nervous System ◽  
Ion Channels ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Diverse Group ◽  
Anion Channels ◽  
C Elegans ◽  
Cholinergic Synapses ◽  
Inhibitory Potential ◽  
Gated Ion Channels

Fast cholinergic neurotransmission is mediated by pentameric acetylcholine-gated ion channels; in particular, cationic nicotinic acetylcholine receptors play well-established roles in virtually all nervous systems. Acetylcholine-gated anion channels have also been identified in some invertebrate phyla, yet their roles in the nervous system are less well-understood. Here we describe the functional properties of five previously-uncharacterized acetylcholine-gated anion channels from C. elegans, including four from a novel nematode specific subfamily known as the diverse group. In addition to their activation by acetylcholine, these diverse group channels are activated at physiological concentrations by other ligands; three, encoded by the lgc-40, lgc-57 and lgc-58 genes, are activated by choline, while lgc-39 encoded channels are activated by octopamine and tyramine. Intriguingly, these and other acetylcholine-gated anion channels show extensive co-expression with cation-selective nicotinic receptors, implying that many cholinergic synapses may have both excitatory and inhibitory potential. Thus, the evolutionary expansion of cholinergic ligand-gated ion channels may enable complex synaptic signalling in an anatomically compact nervous system.

scholarly journals Lynx1 regulates nAChRs to preserve the structure and function of neuromuscular synapses during aging

2020 ◽  
Author(s):  
Sydney V. Doss ◽  
Sébastien Barbat-Artigas ◽  
Tracey Myers ◽  
Bhola Shankar Pradhan ◽  
Tomasz J. Prószyński ◽  
...  
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Neuromuscular Junctions ◽  
Structure And Function ◽  
Neuromuscular Synapses ◽  
Adult Mice ◽  
Homeostatic Synaptic Plasticity ◽  
Age Related ◽  
And Function ◽  
The Brain

AbstractNicotinic acetylcholine receptors (nAChRs) undergo aberrant changes in diseases and with advancing age that compromise the structure and function of neuromuscular junctions (NMJs). Despite this recognition, the mechanisms that regulate muscle nAChRs remain poorly understood. Here, we ask if Lynx1, shown to regulate nAChRs in the brain, plays a similar role at NMJs. We show that Lynx1 concentrates in the postsynaptic region of NMJs where it modulates the function and stability of nAChRs in young adult mice. However, Lynx1 levels decrease at aged NMJs suggesting roles in synaptic maintenance. Supporting this possibility, deletion of Lynx1 prematurely and progressively increases the incidence of NMJs with age-related features, culminating in the atrophy of muscle fibers. These data show that by promoting homeostatic synaptic plasticity and NMJ remodeling, Lynx1 regulation of nAChRs mitigates age-related damages at NMJs.

scholarly journals Drebrin Regulates Acetylcholine Receptor Clustering and Organization of Microtubules at the Postsynaptic Machinery

2021 ◽  
Vol 22 (17) ◽  
pp. 9387
Author(s):  
Paloma Alvarez-Suarez ◽  
Natalia Nowak ◽  
Anna Protasiuk-Filipunas ◽  
Hiroyuki Yamazaki ◽  
Tomasz J. Prószyński ◽  
...  
Keyword(s):  
Actin Cytoskeleton ◽  
Acetylcholine Receptors ◽  
Neuromuscular Junctions ◽  
Microtubule Network ◽  
Postsynaptic Protein ◽  
Cultured Myotubes ◽  
The Brain

Proper muscle function depends on the neuromuscular junctions (NMJs), which mature postnatally to complex “pretzel-like” structures, allowing for effective synaptic transmission. Postsynaptic acetylcholine receptors (AChRs) at NMJs are anchored in the actin cytoskeleton and clustered by the scaffold protein rapsyn, recruiting various actin-organizing proteins. Mechanisms driving the maturation of the postsynaptic machinery and regulating rapsyn interactions with the cytoskeleton are still poorly understood. Drebrin is an actin and microtubule cross-linker essential for the functioning of the synapses in the brain, but its role at NMJs remains elusive. We used immunohistochemistry, RNA interference, drebrin inhibitor 3,5-bis-trifluoromethyl pyrazole (BTP2) and co-immunopreciptation to explore the role of this protein at the postsynaptic machinery. We identify drebrin as a postsynaptic protein colocalizing with the AChRs both in vitro and in vivo. We also show that drebrin is enriched at synaptic podosomes. Downregulation of drebrin or blocking its interaction with actin in cultured myotubes impairs the organization of AChR clusters and the cluster-associated microtubule network. Finally, we demonstrate that drebrin interacts with rapsyn and a drebrin interactor, plus-end-tracking protein EB3. Our results reveal an interplay between drebrin and cluster-stabilizing machinery involving rapsyn, actin cytoskeleton, and microtubules.

scholarly journals Specific heparan sulfate modifications stabilize the synaptic organizer MADD-4/Punctin at C. elegans neuromuscular junctions

Genetics ◽  
2021 ◽  
Author(s):  
Mélissa Cizeron ◽  
Laure Granger ◽  
Hannes E BÜlow ◽  
Jean-Louis Bessereau
Keyword(s):  
Heparan Sulfate ◽  
Matrix Protein ◽  
Neuromuscular Junctions ◽  
Core Protein ◽  
Extracellular Matrix Protein ◽  
Inhibitory Synapses ◽  
Single Chain ◽  
C Elegans ◽  
Sugar Chains

Abstract Heparan sulfate proteoglycans contribute to the structural organization of various neurochemical synapses. Depending on the system, their role involves either the core protein or the glycosaminoglycan chains. These linear sugar chains are extensively modified by heparan sulfate modification enzymes, resulting in highly diverse molecules. Specific modifications of glycosaminoglycan chains may thus contribute to a sugar code involved in synapse specificity. Caenorhabditis elegans is particularly useful to address this question because of the low level of genomic redundancy of these enzymes, as opposed to mammals. Here, we systematically mutated the genes encoding heparan sulfate modification enzymes in C. elegans and analyzed their impact on excitatory and inhibitory neuromuscular junctions. Using single chain antibodies that recognize different heparan sulfate modification patterns, we show in vivo that these two heparan sulfate epitopes are carried by the SDN-1 core protein, the unique C. elegans syndecan orthologue, at neuromuscular junctions. Intriguingly, these antibodies differentially bind to excitatory and inhibitory synapses, implying unique heparan sulfate modification patterns at different neuromuscular junctions. Moreover, while most enzymes are individually dispensable for proper organization of neuromuscular junctions, we show that 3-O-sulfation of SDN-1 is required to maintain wild-type levels of the extracellular matrix protein MADD-4/Punctin, a central synaptic organizer that defines the identity of excitatory and inhibitory synaptic domains at the plasma membrane of muscle cells.

BDNF and nicotine dependence: associations and potential mechanisms

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Zeyi Huang ◽  
Daichao Wu ◽  
Xilin Qu ◽  
Meixiang Li ◽  
Ju Zou ◽  
...  
Keyword(s):  
Nicotine Dependence ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Molecular Mechanisms ◽  
Public Health Problem ◽  
Nicotine Addiction ◽  
Tyrosine Kinase Receptor ◽  
Bdnf Expression ◽  
High Affinity Receptor ◽  
The Brain

AbstractSmoking is the leading preventable cause of death worldwide and tobacco addiction has become a serious public health problem. Nicotine is the main addictive component of tobacco, and the majority of people that smoke regularly develop nicotine dependence. Nicotine addiction is deemed to be a chronic mental disorder. Although it is well known that nicotine binds to the nicotinic acetylcholine receptors (nAChRs) and activates the mesolimbic dopaminergic system (MDS) to generate the pleasant and rewarding effects, the molecular mechanisms of nicotine addiction are not fully understood. Brain-derived neurotrophic factor (BDNF) is the most prevalent growth factor in the brain, which regulates neuron survival, differentiation, and synaptic plasticity, mainly through binding to the high affinity receptor tyrosine kinase receptor B (TrkB). BDNF gene polymorphisms are associated with nicotine dependence and blood BDNF levels are altered in smokers. In this review, we discussed the effects of nicotine on BDNF expression in the brain and summarized the underlying signaling pathways, which further indicated BDNF as a key regulator in nicotine dependence. Further studies that aim to understand the neurobiological mechanism of BDNF in nicotine addcition would provide a valuable reference for quitting smoking and developing the treatment of other addictive substances.

Nicotine as therapeutic agent in treatment of mood disorders

2016 ◽  
Vol 33 (S1) ◽  
pp. S552-S552
Author(s):  
C. Tsopelas ◽  
N. Petros ◽  
D. Maria ◽  
P. Dimitris ◽  
G.G. Angelica ◽  
...  
Keyword(s):  
Mood Disorders ◽  
Acetylcholine Receptors ◽  
Web Search ◽  
Therapeutic Agent ◽  
Negative Attitude ◽  
Medical Databases ◽  
Positive Effects ◽  
Complex Interactions ◽  
Competing Interest ◽  
The Brain

IntroductionThe plant that has as active ingredient nicotine was chewed or smoked for many years from American natives, for its therapeutic properties. Nowadays after the extensive negative attitude towards smoking, the main provider of nicotine, researchers are now pointing out the therapeutic possibilities of nicotine in mood disorders, as a substance that is acting in the acetylcholine receptors in the brain.AimsIn this review we are trying to explore the possibilities of nicotine use as a therapeutic agent.MethodsWe did a detailed research of the main medical databases, and web search engines for relevant studies. We scrutinize them independently, before reaching consensus about appropriateness for inclusion in the study.ResultsDiadermal administration of nicotine has a positive effect in depressive disorder in 3–8 days, an effect that in one study was reversed after cessation of nicotine. Patients with depression and/or healthy subjects show improvement of attention and working memory after diadermal use of nicotine. Research is not conclusive in the sustainability of these positive affects as other researchers emphasize their short effect in mood.ConclusionNicotine presents as part of novel and promising therapeutic agents with complex interactions with other neurotransmitters in the brain. Before condemning nicotine along with smoking we should acknowledge the potential use of nicotine as a therapeutic compound since research shows that some of these positive effects appear not only to smokers after abstinence but also to non-smokers.Disclosure of interestThe authors have not supplied their declaration of competing interest.

scholarly journals Association of beta-cytoplasmic actin with high concentrations of acetylcholine receptor (AChR) in normal and anti-AChR-treated primary rat muscle cultures.

1984 ◽  
Vol 32 (9) ◽  
pp. 973-981 ◽  
Author(s):  
B W Lubit
Keyword(s):  
Acetylcholine Receptor ◽  
Acetylcholine Receptors ◽  
Neuromuscular Junctions ◽  
Morphological Changes ◽  
Muscle Cells ◽  
High Concentration ◽  
Rat Muscle ◽  
Cytoplasmic Actin ◽  
High Concentrations

Previous immunocytochemical studies in which an antibody specific for mammalian cytoplasmic actin was used showed that a high concentration of cytoplasmic actin exists at neuromuscular junctions of rat muscle fibers such that the distribution of actin corresponded exactly to that of the acetylcholine receptors. Although clusters of acetylcholine receptors also are present in noninnervated rat and chick muscle cells grown in vitro, neither the mechanism for the formation and maintenance of these clusters nor the relationship of these clusters to the high density of acetylcholine receptors at the neuromuscular junction in vivo are known. In the present study, a relationship between beta-cytoplasmic actin and acetylcholine receptors in vitro has been demonstrated immunocytochemically using an antibody specific for the beta-form of cytoplasmic actin. Networks of cytoplasmic actin-containing filaments were found in discrete regions of the myotube membrane that also contained high concentrations of acetylcholine receptors; such high concentrations of acetylcholine receptors have been described in regions of membrane-substrate contact. Moreover, when primary rat myotubes were exposed to human myasthenic serum, gross morphological changes, accompanied by an apparent rearrangement of the cytoplasmic actin-containing cytoskeleton, were produced. Although whether the distribution of cytoplasmic actin-containing structures was influenced by the organization of acetylcholine receptor or vice versa cannot be determined from these studies, these findings suggest that in primary rat muscle cells grown in vitro, acetylcholine receptors and beta-cytoplasmic actin-containing structures may be somehow connected.

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