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The Neuromuscular Junction
Published in Nassir H. Sabah, Neuromuscular Fundamentals, 2020
ACh competitive antagonists do not depolarize the membrane; hence, they are termed non-depolarizing blocking agents. d-tubocurarine, a well-known example of a reversible competitive ACh antagonist, is a constituent of curare, a substance that was used by South American Indians to poison their arrows. Its onset is relatively slow, 5 minutes or more, and its action lasts for 1–2 hours. α-bungarotoxin, found in snake venom, is an irreversible competitive ACh antagonist.
Physiology, Biochemistry, and Pathology of Neuromuscular Transmission
Published in Marc H. De Baets, Hans J.G.H. Oosterhuis, Myasthenia Gravis, 2019
Chronic treatment of rats with a-bungarotoxin causes weakness, especially of facial muscles.213,214 Muscle function in TIMG rats can be improved by injection of neostigmine. As expected, the amplitude of MEPPs and the binding of [125I] a-bungarotoxin are reduced in skeletal muscles of TIMG rats. The extent of the reduction of AChRs is dependent on the dose of a-bungarotoxin and the rats can be treated for many months with little risk of death. These features make the TIMG model attractive, especially for studies in which the long-term relationship between AChR reduction and transmitter release is investigated (see below under Secondary effects in the myasthenias).
Nerve-to-Muscle Signals
Published in Peter W. Hochachka, Muscles as Molecular and Metabolic Machines, 2019
Like all channels, the end-plate channel is a glycoprotein, however, more is known of its structure than of any other channel. Before the mid-1960s there were no serious thoughts about the chemical structure of channels in general, and there was certainly no focus on proteins as possible channels. However, by 1973, both the end-plate channel and the Na+ channel were identified as proteins, and their chemical purification was under way. This progress depended on technical developments in protein chemistry and in pharmacology. Methods were appearing for solubilizing and purifying membrane proteins without destroying their function, and selective toxins were being found that bind to the channels with high affinity and that could be used in radioactive form to identify channel molecules during purification. Initial progress gained great impetus from a rich source of end-plate channels: the electric organ of Torpedo, the electic ray. This muscle-derived organ, designed to deliver a high-current shock to prey, is a battery made from stacks of hundreds of cells in series. Each generates a pulse of current through a vast array of AChR channels in response to impulses in a presynaptic cholinergic axon. One whole side of each cell is, in effect, a giant end plate. Another good source of the AChR channel is the electric organ of the electric eel Electrophorus electricus, a teleost fish. Isolation and purification procedures typically use 125I-α-bungarotoxin as an assay for the end-plate channel.
Advances in venom peptide drug discovery: where are we at and where are we heading?
Published in Expert Opinion on Drug Discovery, 2021
Taylor B. Smallwood, Richard J. Clark
Moving away from therapeutic applications, venom-derived peptides are also valuable pharmacological research tools that are improving our understanding of human physiology. Venom peptides are unquestionably the best natural source of potent ion channels modulators and are frequently used to investigate the physiological roles of specific ion channel receptors and their subtypes. The α-bungarotoxin is a neurotoxin peptide from the venom of the banded krait that binds to the postsynaptic nAChR at the neuromuscular junction. The toxin is not used clinically but is an important experimental tool used to study the properties of cholinergic receptors. The high affinity of the toxin to the receptor provided key insights into the structure and mode of action of these receptors, highlighting the importance of nAChRs in both physiology and pathology [113]. Now, a huge diversity of potent and target selective peptides have been isolated from the venom of cone snails, spiders, wasps and scorpions that are being utilized for the elucidation of ion channel function and disease pathology. Given the current foundations, it is anticipated that we are likely to see a rise of venom-derived peptide drugs and believe there is a bright future for venom-derived peptides not only as therapeutics but also as useful research tools.
Quantitative proteomic analysis of venom from Southern India common krait (Bungarus caeruleus) and identification of poorly immunogenic toxins by immune-profiling against commercial antivenom
Published in Expert Review of Proteomics, 2019
Aparup Patra, Abhishek Chanda, Ashis K. Mukherjee
Indian cobra (Naja spp) venom has been shown to contain only post-synaptic neurotoxins [18,30]; however, the occurrence of both pre- and post-synaptic neurotoxins has been reported in Bungarus venom [14,15]. This variation may explain the different pathophysiologies seen in krait and cobra envenomation [54]. The β-bungarotoxin and κ-bungarotoxin (a subtype of 3FTx) representing pre-synaptic neurotoxin and post synaptic neurotoxin, respectively are present in krait venom [14,15]. The proteomic analysis revealed that SI B. caeruleus venom is comprised of a substantial amount of β-bungarotoxin (12.9%) and κ-BTx (5.24%) (Figure 2, Table 1). The β-bungarotoxin causes triphasic effects at the terminus – inhibition initially, a small spike of ACh release, then further inhibition of release. By depleting the ACh vesicles, activation causes the degeneration of the motor nerve terminal [55,56]. The effect of β-bungarotoxins on sphincter pupillae, levator palpebral superioris, neck muscles, bulbar muscles, the limbs, and finally, the diaphragm that leads to respiratory failure, are the primary symptoms of krait envenomation [53]. The κ-BTx affects the neuronal-type of nicotinic cholinoceptors (AChR) at the post-synaptic level in central cholinergic synapses in autonomic ganglia [57]. Because the damage caused by the pre-synaptic neurotoxin is irreversible, the neurological manifestation lasts for 2–3 weeks, as is observed in krait-envenomed patients [53].
An anthocyanin-enriched extract from strawberries delays disease onset and extends survival in the hSOD1G93A mouse model of amyotrophic lateral sclerosis
Published in Nutritional Neuroscience, 2018
Aimee N. Winter, Erika K. Ross, Heather M. Wilkins, Trisha R. Stankiewicz, Tyler Wallace, Keith Miller, Daniel A. Linseman
For gastrocnemius muscle, 18 μm longitudinal sections were cut, collecting every third tissue section on Superfrost coated slides to gain an accurate representation of the size and health of neuromuscular junctions (NMJs). To accomplish this, muscle tissue was fixed for 40 minutes in 4% paraformaldehyde, and then incubated for 1 h in blocking buffer as described above. A 5 μg/ml solution of α-bungarotoxin (BTx) conjugated to Alexa Fluor® 594 (ThermoFisher Scientific Inc., Rockford, IL) was then prepared in blocking buffer containing Hoechst nuclear stain at a dilution of 1:500, and sections were incubated for 1 hour at room temperature. Muscle sections were then washed five times with PBS and sealed with glass cover slips as described above. NMJs were imaged and assessed for size using Adobe Photoshop CS4 software. Size was measured by determining the total area occupied by individual NMJs, and a complete distribution of sizes was created for each of the three treatment groups. At least 50 NMJs per animal were analyzed. NMJs were considered healthy if their morphology was observed to be large and complex, while fragmented and small NMJs were considered to be unhealthy, reflecting a lack of innervation and muscle atrophy.37 This analysis was done on three animals per each of the three treatment groups.