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ABSTRACT: Spontaneous liberation of neurotransmitter quanta is strongly affected by the osmotic pressure of the extracellular fluid. Elevation of the osmolarity by 20-30% increases the rate of release from motor nerve endings by more than one order of magnitude. In this respect the neuromuscular junction resembles some other secretory systems. The mechanism of this hyperosmotic neurosecretion is not yet understood; extracellular calcium ions are not directly responsible, since this effect can be produced in their absence. Recently, it has been suggested that the liberation of neurotransmitter is regulated by the intracellular concentration of free calcium ions. We have therefore examined the hypothesis that hyperosmotic neurosecretion originates from an increase in internal calcium concentration ([Ca]in). At the frog neuromuscular synapse however, it is impossible at present to estimate directly free [Ca]in; hence we used an indirect technique, which is based on two assumptions; first, the frequency of the miniature endplate potentials (m.e.p.p.s.) reflects free [Ca]in. Second, the movement of calcium ions across the presynaptic membrane is governed by the electrochemical gradient, and by the calcium conductance (g(Ca)). If hyperosmotic neurosecretion is caused by an increase in [Ca]in, then increasing g(Ca), under reversed electrochemical gradient for the calcium should cause a reduction in the effect of hyperosmotic stress on transmitter release. We report that hyperosmotic neurosecretion is dependent on [Ca]in.
Nature 06/1977; 267(5607):170-2. · 36.28 Impact Factor
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Cold Spring Harbor Symposia on Quantitative Biology 02/1976; 40:107-16.
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ABSTRACT: 1. The changes in transmitter release produced by mitochondrial inhibitors has been studied at the frog neuromuscular junction using conventional electrophysiological techniques for stimulation and intracellular recording. 2. Inhibitors of the electron transport chain and inhibitors of oxidative phosphorylation produce an increase in the frequency of appearance of the miniature end-plate potentials. This increase in frequency is observed also in calcium-free media. Mitochondrial inhibitors also augment the amount of transmitter liberated by a nerve impulse. 3. Ruthenium red, which is an inhibitor of calcium uptake by mitochondria, increases the spontaneous transmitter release but decreases the quantal content. The latter effect of Ruthenium red is antagonized by calcium. 4. The mitochondrial content of the motor nerve terminals is, on the average, 6.59%. 5. The experimental results are explained on the hypothesis that spontaneous release of transmitter reflects the resting level of intracellular free calcium and the evoked release reflects the sum of the resting calcium and the calcium brought in by the action potential. The mitochondria play a role in transmitter release by participating in the regulation of the intracellular free Ca.
The Journal of Physiology 07/1975; 248(2):285-306. · 4.72 Impact Factor
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The Journal of Physiology 09/1974; 241(1):30P-31P. · 4.72 Impact Factor
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Nature 03/1974; 247(441):478-9. · 36.28 Impact Factor
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ABSTRACT: The effect of Ruthenium Red on synaptic transmission was examined at isolated junctions of the frog, by conventional methods for stimulation and intracellular recording. Ruthenium Red (2.5-10.0 muM) reduces the synaptic potential to subthreshold levels. An analysis of this phenomenon shows that the main action of Ruthenium Red is on the presynaptic nerve terminal where it decreases the number of quanta of transmitter liberated by the nerve impulse. It has the following additional effects: a reduction in the amplitude of the spontaneous miniature end plate potentials; an increase in their frequency; and an increase in delayed release of transmitter after a nerve impulse. Some of these results are discussed in terms of the known inhibitory action of Ruthenium Red on calcium transport across mitochondrial membranes.
Proceedings of the National Academy of Sciences 01/1974; 70(12):3613-6. · 9.68 Impact Factor
