Notes
Neuromuscular Junction Pathophysiology
Sections
Neuromuscle Junction Pathophysiology
Neuromuscle Junction Anatomy
Draw the presynaptic nerve terminal: the knob-like terminal end of an motor axon.
Next, draw the postsynaptic muscle cell membrane (the end-plate); include its junctional folds (which increase the surface area of the postsynaptic membrane).
Label the space between the two cells as the synaptic cleft.
Then, along the crest of the one of the junctional folds, draw a nicotinic acetylcholine receptor, which is a ligand-gated ion channel – we'll soon show how it works.
Now, draw a synaptic vesicle, which is a spherical, membrane-bound organelle.
Show that each vesicle contains ~ 10,000 molecules of acetylcholine (Ach).
- Acetylcholine is synthesized within the nerve terminal from acetyl-CoA and choline.
- For reference, the 10,000 molecules of Ach contained the vesicle are referred to as a quantum.
Next, draw a voltage-gated calcium channel along the presynaptic membrane.
Neuromuscle Transmission & Disorders
Depolarization
Depolarization
Show depolarization along the nerve (this is the first "electrical").
Calcium Influx
Show that it triggers an influx of calcium, which will ultimately trigger the release (the exocytosis) of acetylcholine (which is the "chemical").
- Consider that the greater the influx of calcium, the greater the release of Ach.
Lambert-Eaton Myasthenic Syndrome (LEMS)
For our first pathophysiological condition, indicate that in LEMS there are antibodies directed against the presynaptic P/Q-type voltage-gated calcium channels. Thus, there is a failure of sufficient calcium influx and a weak release of Ach.
Acetylcholine Release
Acetylcholine vesicle docking
Next, draw a SNARE (soluble NSF attachment protein receptor) complex, which helps the synaptic vesicles dock and fuse to the presynaptic cell membrane.
- We can remember that this complex is necessary when we consider that vesicle to presynaptic membrane fusion involves the fusion of two negatively-charge membranes.
Botulism Toxicity
- Now, indicate that botulinum toxin attacks various SNARE proteins, which prevents docking and fusion of the synaptic vesicle.
- Thus, in botulinum toxin, there is reduction/failure of release of acetylcholine.
- For reference: Botulinum A & E attack SNAP-25. Botulinum B, D, F, and G attack VAMP.
Acetylcholine Release
Next, show the release of acetylcholine and show the acetylcholine traverse the synapse and bind to the post-synaptic nicotinic acetylcholine receptor, which, again, are ligand-gated sodium channels.
- For reference, with each depolarization, ~ 100 vesicles are released.
Postsynaptic Excitation
Acetylcholine Binding
So show that acetylcholine binds at two receptor sites and produces a conformational change in the receptor that allows sodium influx.
Postsynaptic Membrane Excitation
Indicate that with enough depolarization, an end-plate potential (EPP) occurs that exceeds the threshold for an action potential (the second "electrical"), and thus an action potential is produced, which progresses along the muscle membrane and ultimately initiates intracellular excitation-contraction coupling, which produces a muscle contraction.
- Consider that miniature end plate potentials (MEPPs) occur when vesicles spontaneously leak into the synaptic cleft and induce small depolarizations that fail to exceed the action potential threshold. In EMG, we record these MEPPs as end plate spikes.
Myasthenia Gravis
Show that in MG, antibodies attack the postsynaptic acetylcholine receptors (or various other related proteins (eg, muscle-specific tyrosine kinase (MuSK)).
Thus, in this disorder, there is normal acetylcholine release but failure of postsynaptic muscle cell depolarization because of a lack of acetylcholine receptors.
Repolarization
Potassium Eflux
Finally, in the presynaptic cell, draw a voltage-gated potassium channel and show that potassium eflux from the cell repolarizes the presynaptic terminal.
Neuromyotonia
Indicate that in neuromyotonia (Isaac's syndrome), there is autoantibody attack against these voltage-gated potassium channels, thus there is failure of repolarization of the presynaptic cell and prolongation of the presynaptic action potential.
This results in stiffness and delayed relaxation of muscle with symptoms of muscle twitching and rippling (myokymia), as well as muscle cramps and functional weakness.
Draw some additional acetylcholine and show that acetylcholinesterase, which is bound to the muscle cell membrane, catalyzes the hydrolysis of acetylcholine.
Show that choline is then taken back up into the presynaptic terminal.
Pharmacological Correlates
Pyridostigmine
Indicate that pyridostigmine is used as an acetylcholinesterase inhibitor for the symptomatic management of myasthenia gravis: it prevents the hydrolysis of Ach.
3,4-diaminopyridine (3,4-DAP)
3,4-diaminopyridine (3,4-DAP), which is used in the management of LEMS, blocks voltage-gated potassium channels, which lengthens depolarization and, thus, augments calcium influx and acetylcholine release.
As a potential side effect, we may be able to predict that 3,4-DAP has the risk of inducing seizures because it prolongs nerve depolarization.
References
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- Hammond, Constance. Cellular and Molecular Neurobiology. Elsevier, 2012.
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- Lindström, Miia, and Hannu Korkeala. "Laboratory Diagnostics of Botulism." Clinical Microbiology Reviews 19, no. 2 (April 2006): 298–314. https://doi.org/10.1128/CMR.19.2.298-314.2006.
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- "Myasthenic Syndromes." Accessed October 31, 2018. https://neuromuscular.wustl.edu/synmg.html.
Nicolle, Michael W. "Myasthenia Gravis and Lambert-Eaton Myasthenic Syndrome," 2016, 28.
- Nigam, P K, and Anjana Nigam. "BOTULINUM TOXIN." Indian Journal of Dermatology 55, no. 1 (2010): 8–14. https://doi.org/10.4103/0019-5154.60343.
- Niks, Erik H, Jan B M Kuks, and Jan J G M Verschuuren. "Epidemiology of Myasthenia Gravis with Anti‐muscle Specific Kinase Antibodies in the Netherlands." Journal of Neurology, Neurosurgery, and Psychiatry 78, no. 4 (April 2007): 417–18. https://doi.org/10.1136/jnnp.2006.102517.
- Perkin, G. David, Douglas C. Miller, Russell J. M. Lane, Maneesh C. Patel, and Fred H. Hochberg. Atlas of Clinical Neurology. Elsevier Health Sciences, 2010.
- Purves, Dale, George J. Augustine, David Fitzpatrick, Lawrence C. Katz, Anthony-Samuel LaMantia, James O. McNamara, and S. Mark Williams. "Release of Transmitters from Synaptic Vesicles." Neuroscience. 2nd Edition, 2001. https://www.ncbi.nlm.nih.gov/books/NBK10866/.
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Südhof, Thomas C., and Klaus Starke. Pharmacology of Neurotransmitter Release. Springer Science & Business Media, 2007.
- Titulaer, Maarten J., Rinse Klooster, Marko Potman, Lidia Sabater, Francesc Graus, Ingrid M. Hegeman, Peter E. Thijssen, et al. "SOX Antibodies in Small-Cell Lung Cancer and Lambert-Eaton Myasthenic Syndrome: Frequency and Relation with Survival." Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology 27, no. 26 (September 10, 2009): 4260–67. https://doi.org/10.1200/JCO.2008.20.6169.