An increase in intracellular Ca2+ is the primary trigger of contraction of gastrointestinal (GI) smooth muscles. However, increasing the Ca2+ sensitivity of the myofilaments by elevating myosin light chain phosphorylation also plays an essential role. Inhibiting myosin light chain phosphatase activity with protein kinase C-potentiated phosphatase inhibitor protein-17 kDa (CPI-17) and myosin phosphatase targeting subunit 1 (MYPT1) phosphorylation is considered to be the primary mechanism underlying myofilament Ca2+ sensitization. The relative importance of Ca2+ sensitization mechanisms to the diverse patterns of GI motility is likely related to the varied functional roles of GI smooth muscles. Increases in CPI-17 and MYPT1 phosphorylation in response to agonist stimulation regulate myosin light chain phosphatase activity in phasic, tonic, and sphincteric GI smooth muscles. Recent evidence suggests that MYPT1 phosphorylation may also contribute to force generation by reorganization of the actin cytoskeleton. The mechanisms responsible for maintaining constitutive CPI-17 and MYPT1 phosphorylation in GI smooth muscles are still largely unknown. The characteristics of the cell-types comprising the neuroeffector junction lead to fundamental differences between the effects of exogenous agonists and endogenous neurotransmitters on Ca2+ sensitization mechanisms. The contribution of various cell-types within the tunica muscularis to the motor responses of GI organs to neurotransmission must be considered when determining the mechanisms by which Ca2+ sensitization pathways are activated. The signaling pathways regulating Ca2+ sensitization may provide novel therapeutic strategies for controlling GI motility. This article will provide an overview of the current understanding of the biochemical basis for the regulation of Ca2+ sensitization, while also discussing the functional importance to different smooth muscles of the GI tract.
Actin Cytoskeleton ; Calcium* ; Gastrointestinal Motility ; Gastrointestinal Tract ; Muscle, Smooth* ; Myofibrils ; Myosin Light Chains ; Myosin-Light-Chain Phosphatase ; Neuroeffector Junction ; Neurotransmitter Agents ; Phosphorylation ; Protein Kinases ; Signal Transduction ; Synaptic Transmission

The vertebrate neuromuscular junction (NMJ) is considered as a “tripartite synapse” consisting of a motor axon terminal, a muscle endplate, and terminal Schwann cells that envelope the motor axon terminal. The neuregulin 1 (NRG1)-ErbB2 signaling pathway plays an important role in the development of the NMJ. We previously showed that Grb2-associated binder 1 (Gab1), a scaffolding mediator of receptor tyrosine kinase signaling, is required for NRG1-induced peripheral nerve myelination. Here, we determined the role of Gab1 in the development of the NMJ using muscle-specific conditional Gab1 knockout mice. The mutant mice showed delayed postnatal maturation of the NMJ. Furthermore, the selective loss of the gab1 gene in terminal Schwann cells produced delayed synaptic elimination with abnormal morphology of the motor endplate, suggesting that Gab1 in both muscles and terminal Schwann cells is required for proper NMJ development. Gab1 in terminal Schwann cells appeared to regulate the number and process elongation of terminal Schwann cells during synaptic elimination. However, Gab2 knockout mice did not show any defects in the development of the NMJ. Considering the role of Gab1 in postnatal peripheral nerve myelination, our findings suggest that Gab1 is a pleiotropic and important component of NRG1 signals during postnatal development of the peripheral neuromuscular system.
Animals ; Mice ; Mice, Knockout ; Motor Endplate ; Muscle, Skeletal* ; Muscles ; Myelin Sheath ; Neuregulin-1 ; Neuromuscular Junction ; Peripheral Nerves ; Presynaptic Terminals ; Protein-Tyrosine Kinases ; Schwann Cells* ; Synapses* ; Vertebrates

No abstract available.
Neuromuscular Junction* ; Physiology*

Muscle relaxants are an irreplaceable item within the modern surgical toolkit. Their almost universal use during surgical procedures of medium-to-long duration means that it is essential that all anesthesiologists must have a comprehensive knowledge of their history and the future prospects for their continued evolution. There are a number of naturally- occurring acetylcholinesterase and butrylcholinesterase inhibitors, including the solanaceous glycoalkaloids (SGAs), which are found in the plants of the family Solanaceae. In the Pharmacopiea of the Philippines indigenous plants, one such plants is Cestrum nocturnum (Dama de Noche). Objective: This experimental animal study was therefore undertaken to determine the neuromuscular effect of the intravenous administered Cestrun nocturnum in an anesthesixed cat. Methods: An N-of-1 A-B-A design in in vivo study was undertaken compairing the effect of the Cestrun Nocturnum ansd atracurium on the neuromuscular junction of an anesthesized cat. Results: Intravenously administered cestrum nocturnum produced an incomplete (40% TOF) but sustained depolarization of the neuromuscular junction that took an hour to fully recover. It also prolonged the onset of atracurium- induced paralysis and delayed its recovey in the pesence of neostigmine. Conclusion: In the light of these findings, we infer that cestrum nocturnum interact with atracurium and neostigmne possibly through pharmacokinetic and pharmacodynamic mechanisms. Further studies are recommended to elucidate these mechanisms.
Animal ; ACETYLCHOLINESTERASE ; SOLANACEAE ; NEUROMUSCULAR JUNCTION

No abstract available.
Motor Endplate*

In 17 myotonic cases (16 of myotonic muscular dystrophy and 1 of congenital myotonia), 13 cases showed significant decremental responses on RNS study. The decremental responses had the tendency of more prominence on faster stimulating rate, and in the proximal limb muscles. This result suggests that the RNS test is useful but not specific for the disorder of neuromuscular junction.
Extremities ; Humans ; Muscles ; Muscular Dystrophies ; Neuromuscular Junction

BACKGROUND: The train of four (TOF) stimulation is valuable to study pharmacodynamics associated with the interaction between muscle relaxants and receptors in the neuromuscular junction. TOF fade expresses presynaptic effect diminished output of transmitters. The aim of this study was to examine differences in presynaptic effects of different relaxants by measuring the TOF ratio during the onset and offset of block. METHODS: Eighty four healthy adult patients of ASA grades I or II were included in the study. The muscle relaxants studied were vecuronium (0.08 mg/kg), atracurium (0.5 mg/kg), mivacurium (0.15 mg/kg), rocuronium (0.6 mg/kg) and succinylcholine (1.0 mg/kg, 0.1 mg/kg, 0.2 mg/kg, 0.4 mg/kg). The TOF ratios were measured at approximate height of first response in the TOF (T1) of 75, 50 and 25% during onset and offset. Especially its ratios were measured at first depress of T1 during onset and its corresponding T1 during offset following administration of subclinical doses of succinylcholine. RESULTS: In the non-depolarizing muscle relaxants, TOF fade is more evident during offset than onset (p<0.05). The extent of fade varies between muscle relaxants. The greatest TOF fade has been shown in rocuronium during onset. In the succinylcholine, the TOF fade is apparent during onset and related to doses given (p<0.05). However the significant TOF fade is not seen during offset. CONCLUSIONS: All muscle relaxants, including both depolarizing and nondepolarizing agent, have predominantly postsynaptic and presynaptic effects. Furthermore, the fact that moderate TOF fade after subclinical doses of succinylcholine occurred obviously during onset of block is possibly indicating a greater presynaptic receptor blocking action.
Adult ; Atracurium ; Humans ; Neuromuscular Blockade* ; Neuromuscular Blocking Agents* ; Neuromuscular Junction ; Neuromuscular Nondepolarizing Agents ; Receptors, Presynaptic ; Succinylcholine ; Vecuronium Bromide

Repetitive nerve stimulation test (RNS) is an easy and non-invasive test which provides objective for the presence of a myasthenic neuromuscular defect and for monitoring possible improvement through various therapeutic measures, and makes the differentiation of neuromuscular junction disorders. Analysing the RNS test of 45 normal controls and 146 patients with myasthenia gravis quantitatively, the following results obtained. 1. At low rate stimulation, the decremental response upto 2 standard deviation in normal control are 7.1% in orbicularis oculi(~), 7.6% in flexor carpi ulnaris (FCU) and 5.4% in abductor digiti guinti muscle(ADQ). There are two kinds of facilitation noticed: incremental responses at repetitive low stimulation (13.3-14.9%) immediately after tetanic stimulationy and increased mean amplitudes of compound muscle action potentials after exercise(l3-17%). Four minutes after the tetanic stimulation, the decremental responses at low rate stimulation become accentuated slightly even in normal control group. 2. At low rate stimulation. There are singificant decremental decremental responses in patients with myasthenia gravis, but statistically no significant differences are seen in the quantity of decremental responses among 2, 3 and 5/sec rate of stimulation. 3. The pattern and severity of decremental responses at low rate stimulation are depending on the clinical type of generalized myasthenia gravis. There are no decremental responses in FCU or ADQ in ocular type. The decremental responses of oo are greater than that of FCU in mild generalize myasthenia, but the reverse is true in moderate generalized type. 4. Statistically significant post-tetanic facilitation and exhaustion are noticed in patients with generalized myasthenia gravis.
Action Potentials ; Humans ; Myasthenia Gravis* ; Neuromuscular Junction Diseases

Repetitive nerve stimulation test (RNS) is an easy and non-invasive test which provides objective for the presence of a myasthenic neuromuscular defect and for monitoring possible improvement through various therapeutic measures, and makes the differentiation of neuromuscular junction disorders. Analysing the RNS test of 45 normal controls and 146 patients with myasthenia gravis quantitatively, the following results obtained. 1. At low rate stimulation, the decremental response upto 2 standard deviation in normal control are 7.1% in orbicularis oculi(~), 7.6% in flexor carpi ulnaris (FCU) and 5.4% in abductor digiti guinti muscle(ADQ). There are two kinds of facilitation noticed: incremental responses at repetitive low stimulation (13.3-14.9%) immediately after tetanic stimulationy and increased mean amplitudes of compound muscle action potentials after exercise(l3-17%). Four minutes after the tetanic stimulation, the decremental responses at low rate stimulation become accentuated slightly even in normal control group. 2. At low rate stimulation. There are singificant decremental decremental responses in patients with myasthenia gravis, but statistically no significant differences are seen in the quantity of decremental responses among 2, 3 and 5/sec rate of stimulation. 3. The pattern and severity of decremental responses at low rate stimulation are depending on the clinical type of generalized myasthenia gravis. There are no decremental responses in FCU or ADQ in ocular type. The decremental responses of oo are greater than that of FCU in mild generalize myasthenia, but the reverse is true in moderate generalized type. 4. Statistically significant post-tetanic facilitation and exhaustion are noticed in patients with generalized myasthenia gravis.
Action Potentials ; Humans ; Myasthenia Gravis* ; Neuromuscular Junction Diseases

Objective To investigate the morphological changes in the degeneration and regeneration of neuromuscular junctions （NMJ） during the repair of mouse skeletal muscle contusion and discuss the correlation between the degeneration and regeneration of NMJ and wound age. Methods A total of 50 healthy adult male mice were randomly divided into 10 groups, including 9 experimental groups and 1 control group. Immunofluorescent staining was applied, and neurofilament was marked with neurofilament protein-H （NF-H）, presynaptic membrane was marked with synaptophysin （Syn）, presynaptic membrane was marked with acetylcholine receptor （AChR）. Morphological changes of NMJ regeneration at different time points after mouse skeletal muscle contusion were detected. Results The neurofilament and presynaptic membrane of NMJ at the junction of contusion zones began to degrade after contusion, and completed degradation at about 3 d post-injury. Then they gradually regenerated, roughly completing the regeneration at about 21 d and basically reaching the control group level. The ratio of presynaptic membrane quantity to presynaptic membrane quantity showed a trend of decreasing then rising and finally reaching the control level. Conclusion During the repair of mouse skeletal muscle contusion, the morphological changes and wound age of the NMJ at the junction of contusion zones have a close correlation, which is expected to be one of the biological indicators for forensic skeletal muscle wound age estimation.
Animals ; Contusions ; Male ; Mice ; Muscle, Skeletal ; Neuromuscular Junction ; Regeneration