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The Neuromuscular Junction
Published in Nassir H. Sabah, Neuromuscular Fundamentals, 2020
The endplate voltage, conventionally referred to as the endplate potential (epp), recorded following a nerve AP is the depolarization caused by the epc acting on the parallel combination of resistance and capacitance of the muscle membrane. The general shape of the epp is illustrated in Figure 5.12. The amplitude of the epp is 50–70 mV above a resting membrane voltage of about –90 mV for the muscle. Since the threshold of the muscle AP is 15–25 mV above the resting voltage, a muscle AP is generated well before the epp reaches its peak. Hence, the full time course of the epp can only be recorded with the muscle AP suppressed. The presence of voltage-gated Na+ channels in the depths of the junctional folds serves to reduce the threshold for the muscle AP. The size of the epp rapidly declines with high-frequency repetitive stimulation of 20–40 APs because of a decrease in the number of vesicles released, but levels off thereafter at about 65% of its size for a single AP. As may be expected, this decline in the size of the epp with repetitive stimulation is more marked at the NMJs of fast muscle fibers compared to those of slow muscle fibers (Section 9.3.2).
Cholinergic Antagonists
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
Vishal S. Gulecha, Manoj S. Mahajan, Aman Upaganlawar, Abdulla Sherikar, Chandrashekhar Upasani
These are the agents that competitively antagonize the action of ACh at the postsynaptic nicotinic receptor (Fig. 2.2). This is a dynamic binding that allows association and dissociation, that is, increased the concentration of ACh than the antagonist results in receptor occupation. With blockade by antagonist, endplate potential decreases gradually until it fails to reach the threshold to generate propagating action potential needed for muscle contraction. Under normal physiological conditions, more transmitter molecules than are needed to generate the endplate potential, evoking a greater than needed response. Simultaneously, only a fraction of the available receptors is used to generate the signal. Neuromuscular transmission, therefore, has a substantial margin of safety (Donati and Bevan, 1996).
Physiology, Biochemistry, and Pathology of Neuromuscular Transmission
Published in Marc H. De Baets, Hans J.G.H. Oosterhuis, Myasthenia Gravis, 2019
The release of ACh by a nerve stimulus can be recorded by electrophysiological methods with good time resolution, provided that the experimental conditions are adjusted with care. A problem that arises with electrophysiological recordings is that upon stimulation of the nerve under normal conditions neuromuscular transmission occurs and the standard spike of the muscle fiber overshadows the electric effect proper of the released neurotransmitter; moreover, the muscle contraction that follows dislodges the microelectrode from the impaled cell. Only when the depolarization caused by the openings of the transmitter receptor channels is reduced below the firing threshold of the muscle fiber it is possible to monitor the so-called “endplate potential” (EPP). In principle, muscle spikes can be avoided or prevented by one of the following methods (see also Glavinovic’57 for the evaluation of the pro’s and contra’s): (1) attenuation of the size of the EPP by application of curare which blocks the AChRs, (2) reduction of the quantal content by exposing the muscle to a low ratio of Ca2+/Mg2+ in the medium, (3) cutting the fibers not far away from the endplates (the “cut muscle” preparation). The resulting steady depolarization of the muscle stumps (around -35 mV) causes inactivation of the voltage-dependent Na+ channels of the muscle fiber, and (4) treating the preparation with μ-conotoxin. This substance prevents muscle spikes by blocking Na+ channels of the muscle without blocking those of the nerve.
Advances in autoimmune myasthenia gravis management
Published in Expert Review of Neurotherapeutics, 2018
Shuhui Wang, Iva Breskovska, Shreya Gandhy, Anna Rostedt Punga, Jeffery T. Guptill, Henry J. Kaminski
Regardless of the autoantibody type, the underlying physiological abnormality leading to skeletal muscle weakness is the reduction of the safety factor for neuromuscular transmission [29,30]. The safety factor is the difference in the endplate potential and the threshold potential required to generate an action potential, which will then trigger contraction of the muscle fiber. Whether there are AChR, MuSK, or no other autoantibody presently detected, the reduction of AChR is the primary contributor to a reduced endplate potential. Loss of synaptic folds and post-synaptic sodium channels serve to reduce the safety factor further. This tenuous situation of low safety factors among neuromuscular junctions across all skeletal muscle in a patient leads to the variability in weakness depending on the level of activity, degree of damage, temperature, and unknown factors produces the characteristic fatigable weakness that patients experience. Repetitive neuronal activity leads to a small reduction in release of acetylcholine, which under normal conditions is unimportant, but at the myasthenic junction can reduce the endplate potential that is required for action potential generation with consequent reduced muscle force generation and weakness. The basal lamina of the synaptic cleft is concentrated with acetylcholinesterase (AChE), which serves to terminate the activity of acetylcholine released from the presynaptic nerve terminal. AChE inhibition increases the available acetylcholine for binding to the AChR, thereby increasing the endplate potential and improving a compromise of the safety factor.
Sensory neurotization of muscle: past, present and future considerations
Published in Journal of Plastic Surgery and Hand Surgery, 2019
Steven D. Kozusko, Alexander J. Kaminsky, Louisa C. Boyd, Petros Konofaos
There are a few contraindications reported for sensory neurotization. If the period of denervation time is substantial then permanent muscle atrophy with loss of end-plate potential precludes efficacy of sensory neurotization. If the muscle has been severely damaged and restoration of neuronal input would have no functional recovery then sensory neurotization is inappropriate. Lastly, if the extremity is severely damaged or there is marked joint stiffness and fibrotic muscles then sensory neurotization would not provide substantial benefit [27].