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Biomedical subjects

R Miledi

Publications and source records attributed to R Miledi.

At least 271 records · Page 15Linked to original sources
PubMed1975

A presynaptic complex in the giant synapse of the squid.

A presynaptic complex consisting of thin lamellae associated with vesicles was found frequently in presynaptic terminals of the squid giant synapse. The lamellae, made of osmiophilic material, had an average length and width of about 10 mum and a thickness of 30 nm; they were of rectangular shape. While most frequent in the axoplasm of the most distal, and largest, terminal of the presynaptic giant axon, the lamellae were found also in smaller terminal branches of this fibre; They have not been observed in the proximal parts of the presynaptic or postsynaptic giant axons. Vesicles the size of synaptic vesicles surrounded the sides of the lamellae. The presynaptic complex resembles the synaptic ribbons in sensory cells.

Animals↗
PubMed1975

The effect of procaine on the action of acetylcholine at the neuromuscular junction.

1. The effect of procaine on acetylcholine-induced membrane fluctuations (ACh noise) was studied by intracellular and focal external recording from end-plates of frog sartorius muscle. 2. With intracellular recording, ACh noise (the ratio of variance to mean depolarization) was substantially reduced by procaine, suggesting a greatly decreased amplitude of the elementary potential change. 3. Spectral analysis of the ACh noise indicated a dual average time course of the underlying "shot effects", similar to the complex shape (brief spike followed by a long tail of low intensity) of the end-plate current in pro-aine-treated muscle. 4. The post-synaptic blocking action of procaine can be largely explained by the drastic shortening of the initial high-intensity phase of the end-plate conductance change. 5. The average time course of the ACh shot effects is discussed in terms of alternative hypotheses, one attributing the complex shape to each elementary event, the other involving sequential reaction steps which produce two unequal populations of ion gates of different "life-times".

Acetylcholine↗
PubMed1974

Electrically induced release of acetylcholine from denervated Schwann cells.

1. Focal electrical stimulation of Schwann cells at the end-plates of denervated frog muscles elicited slow depolarizations of up to 30 mV in the muscle fibres. This response is referred to as a Schwann-cell end-plate potential (Schwann-e.p.p.).2. Repeated stimulation sometimes evoked further Schwann-e.p.p.s, but they were never sustained for more than 30 pulses. Successive e.p.p.s varied in amplitude and time course independently of the stimulus.3. The Schwann-e.p.p.s were reversibly blocked by curare, suggesting that they result from a release of acetylcholine (ACh) by the Schwann cells.4. ACh release by electrical stimulation did not seem to occur in quantal form and was not dependent on the presence of calcium ions in the external medium; nor was it blocked by tetrodotoxin.5. Stimulation which caused release of ACh also resulted in extensive morphological disruption of the Schwann cells, as seen with both light and electron microscopy.6. It is concluded that electrical stimulation of denervated Schwann cells causes break-down of the cell membrane and releases ACh, presumably in molecular form.

Acetylcholine↗
PubMed1974

Non-transmitting neuromuscular junctions during an early stage of end-plate reinnervation.

1. Electrophysiological studies were made on regenerating motor end-plates in frog cutaneous pectoris muscle after crushing the motor nerve.2. The pattern of degenerative and regenerative changes is similar to that already described for the frog sartorius, although it occurs more quickly in the cutaneous pectoris. Resumption of synaptic transmission first occurs after 9 days, in muscle fibres closest to the nerve crush. During the subsequent 12 days synaptic contact is progressively re-established across the muscle.3. During the period of regeneration muscle fibres can be found which have been reinnervated, but which do not produce an end-plate potential in response to stimulation of the nerve trunk. This is referred to as the ;non-transmitting' stage of regeneration.4. Increases in extracellular potassium, addition of lanthanum to the bath and focal extracellular stimulation all indicate that the axon terminals at non-transmitting junctions do have a releasable supply of neurotransmitter. Focal stimulation occasionally sets up active responses in these nerve terminals.5. It is concluded that this ;non-transmitting' stage results from failure of action potential propagation in the regenerating neurone proximal to the end-plate region.

Animals↗
PubMed1974

Characteristics of transmitter release at regenerating frog neuromuscular junctions.

1. A study was made of the onset of transmission and the characteristics of transmitter release from regenerating nerve terminals in frog muscle fibres.2. Soon after transmission had been restored, some junctions were found which responded to nerve stimulation with only subthreshold end-plate potentials.3. The evoked transmitter release had a non-linear dependence on the external calcium concentration, like that seen at normal junctions.4. The synaptic delay was only slightly longer than normal, and the amplitudes of single quantum potentials evoked by nerve stimulation seemed to have a normal distribution.5. The mean amplitude of the spontaneous miniature end-plate potentials was often substantially smaller than the mean amplitude of the evoked quantal potentials at a given end-plate. Some of these small spontaneous potentials were due to transmitter release from the axon terminal. Possible explanations for this discrepancy in size of spontaneous and evoked potentials are discussed. Two to three weeks after reinnervation began, the amplitude of the spontaneous miniature end-plate potentials returned to normal.

Animals↗
PubMed1974

Absence of action potentials in frog slow muscle fibres paralysed by botulinum toxin.

1. As shown previously, slow muscle fibres of the frog develop the ability to produce action potentials in 2 weeks after denervation.2. Normal transmission at the slow fibre neuromuscular junction gives a junction potential of 11 mV average (range 6-20 mV), caused by summation of potentials from several motor axons.3. Botulinum toxin injected intramuscularly into the iliofibularis blocks the neuromuscular junction of slow fibres in 6 days at room temperature. Single nerve stimuli give junction potentials of 0.05 mV average (range 0-1.6 mV). Contraction of slow fibres in response to tetanic stimulation is eliminated.4. No action potentials could be elicited in botulinum treated fibres, even 6(1/2) weeks after injection of toxin. This finding is discussed in relation to the possible involvement of a ;trophic' factor regulating the action potential mechanism in frog slow muscle fibres.

Action Potentials↗
PubMed1973

The effect of alpha-bungarotoxin on acetylcholine receptors.

Fluctuations of membrane potential ('membrane noise') during acetylcholineinduced depolarization have been studied by intracellular recording from endplates of frog muscle fibres. When acetylcholine sensitivity had been greatly reduced by an irreversible inhibitor (alpha-bungarotoxin), analysis of the membrane noise showed that neither the amplitude nor the time course of the 'elementary' potential change (due to the molecular depolarizing action of acetylcholine) were altered.

Acetylcholine↗
PubMed1973

The characteristics of 'end-plate noise' produced by different depolarizing drugs.

1. End-plate depolarization and associated ;membrane noise' due to decamethonium, acetylthiocholine and suberyldicholine have been examined and compared with the effects of acetylcholine and carbachol.2. The transient ionic channels resulting from the action of decamethonium and acetylthiocholine are of much shorter duration than those produced by acetylcholine. They are, therefore, similarly to carbachol channels, less effective in causing membrane depolarization.3. Suberyldicholine, on the other hand, produces ion channels whose duration exceeds that of acetylcholine.4. Lowering the temperature causes an increase in amplitude of the elementary potential change produced by decamethonium and acetylthiocholine.5. The relation between the characteristic features of drug-induced membrane noise and the underlying molecular reaction rates is discussed.

Acetylcholine↗
PubMed1973

The binding of acetylcholine to receptors and its removal from the synaptic cleft.

1. Acetylcholine (ACh) noise and miniature end-plate potentials were recorded with focal external micro-electrodes.2. The effect of prostigmine on the time course of the ;molecular' and ;quantal' transmitter actions was studied. Prostigmine (10(-6) g/ml.) has little or no effect on the duration of the molecular ;gating action', while it greatly prolongs the quantal conductance change.3. After inhibition of ACh hydrolysis, the removal of the transmitter from the synapse is generally too slow to be accounted for by free diffusion. It is suggested that diffusion is delayed by binding to post-synaptic receptors. This is consistent with the finding that receptor blockage by curare or alpha-bungarotoxin shortens as well as reduces quantal transmitter action.4. The correlated effects of the receptor-blocking agents, on size and time course of the miniature end-plate currents, were subjected to a simple analysis. Its result suggests that after inhibition of cholinesterase about two thrids of the quantal packet of ACh combines with post-synaptic receptors.5. During focal external recording the effect of prostigmine on the time course of miniature end-plate potentials can become exaggerated due to what appears to be a compression artifact which obstructs outward diffusion of the transmitter.

Acetylcholine↗
PubMed1972

A study of frog muscle maintained in organ culture.

1. Frog muscles are isolated and maintained in organ culture conditions for periods of up to 2 months. During the first 2 weeks, muscle fibres have normal resting membrane and action potentials. Subsequently the potentials decline in amplitude.2. Slow muscle fibres also survive in culture and retain their ability to give maintained contractures.3. Muscle sensory receptors continue to function in culture until the axon terminals degenerate at about 2 weeks.4. Neuromuscular transmission is normal during the first few days of culture, after which the motor endings degenerate. Transmission persists longer (up to 17 days) if a long segment of nerve is left attached to the muscle. With short-nerve preparations failure of transmission in vivo occurs at about the same time as in culture. With long-nerve preparations failure of transmission is delayed even further in culture.5. In short-nerve preparations miniature end-plate potentials disappear, in general, at about the time that transmission fails. In long-nerve preparations some end-plates continue to have miniature end-plate potential activity for a short time after nerve impulses cease to evoke any response; but eventually miniature potential activity disappears from all end-plates.6. After a few days of electrical silence, miniature end-plate potentials reappear at some of the denervated end-plates. The proportion of denervated end-plates which show miniature end-plate potentials in culture is smaller than in muscles denervated in situ.7. Electron microscopy shows that muscle structure is well preserved in culture, that the axons degenerate and that the Schwann cells move to occupy the space vacated by the axons. The Schwann cells are very probably the source of the acetylcholine which evokes miniature potentials in the denervated end-plates.

Acetylcholine↗