Structural evidence that botulinum toxin blocks neuromuscular transmission by impairing the calcium influx that normally accompanies nerve depolarization.

Hirokawa, Nobutaka; Heuser, John E.

doi:10.1083/jcb.88.1.160

Cited by 51 publications

(12 citation statements)

References 40 publications

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“…The exact mechanisms by which these three phenomena can be explained remain to be shown, but several possibilities should be addressed. First, the Purkinje cell terminals in tg contain the mutated P/Q-type Ca 2+ -channels and thereby they will most likely directly show altered dynamics and kinetics of their vesicle release, which in turn may influence the constitution of the organelles inside them [32][33][34][35]. Second, the increased irregularity of Purkinje cell firing in tg contributes to the occurrence of high frequency bursts of simple spikes [9].…”

Section: Discussionmentioning

confidence: 99%

Purkinje Cell Input to Cerebellar Nuclei in Tottering: Ultrastructure and Physiology

et al. 2008

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Homozygous tottering mice are spontaneous ataxic mutants, which carry a mutation in the gene encoding the ion pore of the P/Q-type voltage-gated calcium channels. P/Q-type calcium channels are prominently expressed in Purkinje cell terminals, but it is unknown to what extent these inhibitory terminals in tottering mice are affected at the morphological and electrophysiological level. Here, we investigated the distribution and ultrastructure of their Purkinje cell terminals in the cerebellar nuclei as well as the activities of their target neurons. The densities of Purkinje cell terminals and their synapses were not significantly affected in the mutants. However, the Purkinje cell terminals were enlarged and had an increased number of vacuoles, whorled bodies, and mitochondria. These differences started to occur between 3 and 5 weeks of age and persisted throughout adulthood. Stimulation of Purkinje cells in adult tottering mice resulted in inhibition at normal latencies, but the activities of their postsynaptic neurons in the cerebellar nuclei were abnormal in that the frequency and irregularity of their spiking patterns were enhanced. Thus, although the number of their terminals and their synaptic contacts appear quantitatively intact, Purkinje cells in tottering mice show several signs of axonal damage that may contribute to altered postsynaptic activities in the cerebellar nuclei.

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Section: Discussionmentioning

confidence: 99%

Purkinje Cell Input to Cerebellar Nuclei in Tottering: Ultrastructure and Physiology

et al. 2008

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“…The swelling of mitochondria after injury results from the entry of solutes and water into the mitochondrial matrix. 9 In severe swelling, the mitochondria are transformed into structureless vacuoles that contribute to the vacuolar appearance of swollen cells. When primary injury to mitochondria is the cause of swelling, these organelles may be massively enlarged.…”

Section: Discussionmentioning

confidence: 99%

Neurohistologic and Ultrastructural Lesions in Cattle Experimentally Intoxicated with the Plant Prosopis juliflora

et al. 2006

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Abstract. Intoxication by pods of Prosopis juliflora (mesquite beans) causes an impairment of cranial nerve function in cattle and goats. In goats, vacuolation of neurons in the trigeminal motor nuclei has been reported. To study the lesions in cattle caused by consumption of P. juliflora pods and dry ground pods, eight 6-to 12-month-old male cattle were divided into 4 groups: group 1 was fed a ration containing 50% of pods; groups 2 and 3 received a ration containing 50 and 75% of dry ground pods, respectively; group 4 was the control. After 200 days, all cattle were killed and sampled for histologic evaluation. Samples of the trigeminal motor nucleus were examined by electron microscopy. All cattle from groups 1, 2, and 3 showed clinical signs resulting from impaired function of cranial nerves V, IX, X, and XII, starting 45-75 days after consumption of the plant. The main histologic lesions were vacuolation and loss of neurons in trigeminal motor nuclei and other motor cranial nerve nuclei with Wallerian-like degeneration in the cranial nerves. Mild denervation atrophy was observed in the masseter and other masticatory muscles. On electron microscopy, neurons of the trigeminal nuclei had markedly swollen mitochondria, with the mitochondrial cristae displaced peripherally, disoriented and disintegrating. Intoxication by P. juliflora seems to have a novel pathogenesis, characterized by a selective, primary, chronic, and progressive injury to mitochondria of neurons of the trigeminal and other cranial nerve nuclei. Cranial nerve degeneration and denervation atrophy of the muscles occurs as a consequence of the neuronal lesion.

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“…Figure 1 illustrates a longitudinal-section of a frog neuromuscular iunction that was freeze-substituted after quick-freezing. This method preserves the natural contours of nerve and muscle membranes and the membranes of their internal organelles (Hirokawa & Kirino, 1980;Hirokawa & Heuser, 1981a). The muscle membrane opposite the nerve terminal is thrown into folds which occur in between bulbous sarcoplasrnic projections.…”

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confidence: 99%

“…Other cutaneous pectoris muscles were quick-frozen directly from life without any treatment. These were later transferred into 100% acetone containing 5% OsO4 for 2-3 days at -90 ~ C. Then they were warmed stepwise, first to -20 ~ C for 2 h and finally to 4 ~ C for 2 h (Hirokawa & Kirino, 1980;Hirokawa & Heuser, 1981a). At this point they were washed with 100% ethanol at 4 ~ C, allowed to warm to room temperature, and block-stained for 2 h with 2% uranyl acetate in 100% ethanol.…”

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confidence: 99%

Internal and external differentiations of the postsynaptic membrane at the neuromuscular junction

1982

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Frog, snake and rat neuromuscular junctions were prepared for electron microscopy by the quick-freeze, deep-etch, rotary replication procedure. The postsynaptic membrane was exposed by treating muscles with 1 mg/ml collagenase to remove the basal lamina. Present on the apices of the postsynaptic folds are regular arrays of 8-9 nm protrusions. These are not seen in the depths of the folds nor elsewhere on the muscle surface, thus they presumably represent the heads of cholinergic receptor molecules. These protrusions tend to be arranged in parallel rows two-abreast. Their high concentration (10 000/microns2) and their orderly arrangement is basically similar to the receptors seen in Torpedo postsynaptic membrane. Their distribution did not appear to change after denervation. Efforts were made to expose possible anchoring structures of these receptors, by treating muscles with 0.1% Saponin immediately before and/or during fixation in 1% formaldehyde, or by homogenizing muscles after brief formaldehyde fixation. This washed most soluble protein out of the cytoplasm and exposed a submembraneous meshwork just beneath the postsynaptic membrane. This meshwork appears to connect the membrane to underlying bundles of intermediate filaments which course through the postsynaptic processes that border each fold. This meshwork is presumably equivalent to the postsynaptic 'density' seen in thin sections. Its three-dimensional structure suggests that it could anchor receptor molecules to underlying cytoskeletal elements and thus immobilize receptors in the plane of the postsynaptic membrane.

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Structural evidence that botulinum toxin blocks neuromuscular transmission by impairing the calcium influx that normally accompanies nerve depolarization.

Cited by 51 publications

References 40 publications

Purkinje Cell Input to Cerebellar Nuclei in Tottering: Ultrastructure and Physiology

Purkinje Cell Input to Cerebellar Nuclei in Tottering: Ultrastructure and Physiology

Neurohistologic and Ultrastructural Lesions in Cattle Experimentally Intoxicated with the Plant Prosopis juliflora

Internal and external differentiations of the postsynaptic membrane at the neuromuscular junction

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