Cholesterol and the Safety Factor for Neuromuscular Transmission

A present review is devoted to the analysis of literature data and results of own research. Skeletal muscle neuromuscular junction is specialized to trigger the striated muscle fiber contraction in response to motor neuron activity. The safety factor at the neuromuscular junction strongly depends on a variety of pre- and postsynaptic factors. The review focuses on the crucial role of membrane cholesterol to maintain a high efficiency of neuromuscular transmission. Cholesterol metabolism in the neuromuscular junction, its role in the synaptic vesicle cycle and neurotransmitter release, endplate electrogenesis, as well as contribution of cholesterol to the synaptogenesis, synaptic integrity, and motor disorders are discussed.

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Neuromuscular Junction Disorders

10.1093/med/9780197512166.003.0088 ◽

2021 ◽

pp. 772-778

Author(s):

Brent P. Goodman

Keyword(s):

Neuromuscular Junction ◽

Action Potential ◽

Motor Unit ◽

Safety Factor ◽

Muscle Fiber ◽

Nerve Terminal ◽

Neuromuscular Transmission ◽

Critical Component ◽

End Plate ◽

Unmyelinated Nerve

The neuromuscular junction (NMJ) is a critical component of the motor unit that is made up of the distal, unmyelinated nerve terminal, synaptic space, and end-plate region of the muscle fiber. Contraction of muscle fiber involves a coordinated series of steps that ultimately generates an action potential at the muscle end plate (also known as an end-plate potential). Normally the end-plate potential substantially exceeds the threshold necessary to trigger an action potential in the muscle fiber, and this difference is termed the safety factor of neuromuscular transmission. Disorders that affect the NMJ reduce this safety factor, a change that results in fatigable weakness.

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Enhancement of transmission at the frog neuromuscular junction by adenosine deaminase: Evidence for an inhibitory role of endogenous adenosine on neuromuscular transmission

Neuroscience Letters ◽

10.1016/0304-3940(85)90366-0 ◽

1985 ◽

Vol 62 (2) ◽

pp. 267-270 ◽

Cited By ~ 23

Author(s):

A.M. Sebastiào ◽

J.A. Ribeiro

Keyword(s):

Neuromuscular Junction ◽

Adenosine Deaminase ◽

Neuromuscular Transmission ◽

Frog Neuromuscular Junction ◽

Endogenous Adenosine ◽

Inhibitory Role

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Case 17

10.1093/med/9780190603434.003.0021 ◽

2018 ◽

Author(s):

Bashar Katirji

Keyword(s):

Neuromuscular Junction ◽

Myasthenia Gravis ◽

Nerve Stimulation ◽

Neuromuscular Transmission ◽

Diagnostic Sensitivity ◽

Repetitive Nerve Stimulation ◽

Tensilon Test ◽

Diagnostic Modalities ◽

Ice Pack

Myasthenia gravis is a relatively common neuromuscular junction disorder. The diagnosis of myasthenia gravis may be challenging particularly in seronegative patients. This case starts by discussing the diagnostic modalities available to confirm the diagnosis of myasthenia gravis including serum antibodies, the Tensilon test, and the ice pack test. After a detailed discussion of the physiology of neuromuscular transmission, the case emphasizes the role of electrodiagnostic studies in the diagnosis of myasthenic gravis. This includes detailed findings on repetitive nerve stimulation recording distal and proximal muscles as well as single-fiber electromyography jitter studies. Finally, the diagnostic sensitivity of the available tests in myasthenia gravis is compared and a suggested electrodiagnostic strategy for patients with suspected myasthenic gravis is outlined.

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Modulatory Roles of ATP and Adenosine in Cholinergic Neuromuscular Transmission

International Journal of Molecular Sciences ◽

10.3390/ijms21176423 ◽

2020 ◽

Vol 21 (17) ◽

pp. 6423

Author(s):

Ayrat U. Ziganshin ◽

Adel E. Khairullin ◽

Charles H. V. Hoyle ◽

Sergey N. Grishin

Keyword(s):

Safety Factor ◽

Neuromuscular Transmission ◽

Synaptic Cleft ◽

Cholinergic Receptors ◽

P2 Receptor ◽

Physiological Conditions ◽

Endogenous Modulators

A review of the data on the modulatory action of adenosine 5’-triphosphate (ATP), the main co-transmitter with acetylcholine, and adenosine, the final ATP metabolite in the synaptic cleft, on neuromuscular transmission is presented. The effects of these endogenous modulators on pre- and post-synaptic processes are discussed. The contribution of purines to the processes of quantal and non-quantal secretion of acetylcholine into the synaptic cleft, as well as the influence of the postsynaptic effects of ATP and adenosine on the functioning of cholinergic receptors, are evaluated. As usual, the P2-receptor-mediated influence is minimal under physiological conditions, but it becomes very important in some pathophysiological situations such as hypothermia, stress, or ischemia. There are some data demonstrating the same in neuromuscular transmission. It is suggested that the role of endogenous purines is primarily to provide a safety factor for the efficiency of cholinergic neuromuscular transmission.

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EXPERIMENTS ON THE ROLE OF POTASSIUM IN THE BLOCKING OF NEUROMUSCULAR TRANSMISSION BY CURARE AND OTHER DRUGS

The Journal of General Physiology ◽

10.1085/jgp.34.5.607 ◽

1951 ◽

Vol 34 (5) ◽

pp. 607-617

Author(s):

Wallace O. Fenn ◽

Rebeca Gerschman ◽

George Fischer ◽

Jane Lacy ◽

Margaret D. Bailly ◽

...

Keyword(s):

Neuromuscular Junction ◽

Cation Exchange ◽

Muscle Tissue ◽

Neuromuscular Transmission ◽

Previous Treatment ◽

Small Loss ◽

Ringer’S Solution ◽

Negative Results ◽

Potassium Compound

1. Experiments with perfused frog muscles and with isolated frog muscles immersed in Ringer's solution have failed to show any effect of curare in liberating potassium from muscle tissue. This makes it difficult to suppose that the paralytic effect of curare can be attributed to cation exchange between curare and K whereby a labile potassium compound needed for stimulation is removed from the neuromuscular junction. 2. Similar negative results were obtained with dihydro-ß-erythroidine and myanesin. 3. A small liberation of K from perfused muscle does result from treatment with acetylcholine. This is probably due to the contracture of the muscle since the effect is largely eliminated by previous treatment of the muscle with curare. The amount of potassium lost in this way from perfused muscles is too small to detect when muscles are analyzed after immersion in Ringer's solution with and without acetylcholine. It is concluded that there is no significant cation exchange between acetylcholine and K in muscle, but only a small loss of K due to the contracture produced by the acetylcholine.

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POPDC proteins and cardiac function

Biochemical Society Transactions ◽

10.1042/bst20190249 ◽

2019 ◽

Vol 47 (5) ◽

pp. 1393-1404 ◽

Cited By ~ 4

Author(s):

Thomas Brand

Keyword(s):

Potential Role ◽

Striated Muscle ◽

Short Review ◽

Effector Proteins ◽

Muscle Disease ◽

Disease Genes ◽

Protein Protein Interaction ◽

Interaction Partners ◽

And Function

Abstract The Popeye domain-containing gene family encodes a novel class of cAMP effector proteins in striated muscle tissue. In this short review, we first introduce the protein family and discuss their structure and function with an emphasis on their role in cyclic AMP signalling. Another focus of this review is the recently discovered role of POPDC genes as striated muscle disease genes, which have been associated with cardiac arrhythmia and muscular dystrophy. The pathological phenotypes observed in patients will be compared with phenotypes present in null and knockin mutations in zebrafish and mouse. A number of protein–protein interaction partners have been discovered and the potential role of POPDC proteins to control the subcellular localization and function of these interacting proteins will be discussed. Finally, we outline several areas, where research is urgently needed.

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Clustering-Triggered Efficient Room Temperature Phosphorescence from Nonconventional Luminophores

10.26434/chemrxiv.9959132 ◽

2019 ◽

Author(s):

Shuyuan Zheng ◽

Taiping Hu ◽

Xin Bin ◽

Yunzhong Wang ◽

Yuanping Yi ◽

...

Keyword(s):

Room Temperature ◽

High Efficiency ◽

Spin Orbit Coupling ◽

Design Rationale ◽

Emission Mechanism ◽

Room Temperature Phosphorescence ◽

Electronic Interactions ◽

Energy Gaps ◽

Theoretical Results

Pure organic room temperature phosphorescence (RTP) and luminescence from nonconventional luminophores have gained increasing attention. However, it remains challenging to achieve efficient RTP from unorthodox luminophores, on account of the unsophisticated understanding of the emission mechanism. Here we propose a strategy to realize efficient RTP in nonconventional luminophores through incorporation of lone pairs together with clustering and effective electronic interactions. The former promotes spin-orbit coupling and boost the consequent intersystem crossing, whereas the latter narrows energy gaps and stabilizes the triplets, thus synergistically affording remarkable RTP. Experimental and theoretical results of urea and its derivatives verify the design rationale. Remarkably, RTP from thiourea solids with unprecedentedly high efficiency of up to 24.5% is obtained. Further control experiments testify the crucial role of through-space delocalization on the emission. These results would spur the future fabrication of nonconventional phosphors, and moreover should advance understanding of the underlying emission mechanism.<br>

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Abnormal brain cholesterol homeostasis in Alzheimer’s disease—a targeted metabolomic and transcriptomic study

npj Aging and Mechanisms of Disease ◽

10.1038/s41514-021-00064-9 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Vijay R. Varma ◽

H. Büşra Lüleci ◽

Anup M. Oommen ◽

Sudhir Varma ◽

Chad T. Blackshear ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Brain Tissue ◽

Cholesterol Metabolism ◽

Cholesterol Biosynthesis ◽

Cholesterol Homeostasis ◽

Transcriptomic Data ◽

Brain Cholesterol ◽

Cholesterol Levels

AbstractThe role of brain cholesterol metabolism in Alzheimer’s disease (AD) remains unclear. Peripheral and brain cholesterol levels are largely independent due to the impermeability of the blood brain barrier (BBB), highlighting the importance of studying the role of brain cholesterol homeostasis in AD. We first tested whether metabolite markers of brain cholesterol biosynthesis and catabolism were altered in AD and associated with AD pathology using linear mixed-effects models in two brain autopsy samples from the Baltimore Longitudinal Study of Aging (BLSA) and the Religious Orders Study (ROS). We next tested whether genetic regulators of brain cholesterol biosynthesis and catabolism were altered in AD using the ANOVA test in publicly available brain tissue transcriptomic datasets. Finally, using regional brain transcriptomic data, we performed genome-scale metabolic network modeling to assess alterations in cholesterol biosynthesis and catabolism reactions in AD. We show that AD is associated with pervasive abnormalities in cholesterol biosynthesis and catabolism. Using transcriptomic data from Parkinson’s disease (PD) brain tissue samples, we found that gene expression alterations identified in AD were not observed in PD, suggesting that these changes may be specific to AD. Our results suggest that reduced de novo cholesterol biosynthesis may occur in response to impaired enzymatic cholesterol catabolism and efflux to maintain brain cholesterol levels in AD. This is accompanied by the accumulation of nonenzymatically generated cytotoxic oxysterols. Our results set the stage for experimental studies to address whether abnormalities in cholesterol metabolism are plausible therapeutic targets in AD.

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