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Biomedical subjects

F Dreyer

Publications and source records attributed to F Dreyer.

At least 55 records · Page 3Linked to original sources
PubMed1981

Different effects of botulinum A toxin and tetanus toxin on the transmitter releasing process at the mammalian neuromuscular junction.

The quantal transmitter release of tetanus (TeTx) and botulinum A (BoTx) toxin paralyzed mouse diaphragms was studied. The very low release probability could be enhanced by increasing the frequency of nerve stimulation to 50 Hz or by the application of 4-aminopyridine. In the BoTx-muscles the endplate potentials were strongly coupled to the stimuli with synaptic delays similar to unpoisoned terminals. In contrast, in the TeTx-muscles large variations in the delay of release of quanta in response to stimulation were observed. From these findings it is suggested that TeTx and BoTx act at different sites of the depolarization-transmitter release process.

Animals↗
PubMed1981

At least three sequential steps are involved in the tetanus toxin-induced block of neuromuscular transmission.

Tetanus toxin causes a block of the neuromuscular transmission. The kinetic aspects of the block were studied in vitro on the mouse phrenic nerve-hemidiaphragm exposed to toxin (1 microgram/ml). 1. The toxin action on the nerve ending involves three sequential steps: binding, "translocation" and paralysis. 2. Diffusion and binding of tetanus toxin molecules to the presynaptic membrane is complete in about 60 min. The binding step is irreversible, independent of transmitter release and of the temperature. Tetanus antitoxin, however, inactivates the bound toxin molecules. 3. After a second step which is probably due to a "translocation" of the toxin molecules into or through the presynaptic membrane the antitoxin molecules are now ineffective to prevent the toxin-induced inhibition of transmitter release. This so called "translocation" step requires transmitter release and therefore depends strongly on the frequency of nerve stimulation. 4. The paralytic step does not depend on the transmitter release. It, however, depends strongly on temperature with a break in the Arrhenius-plot around 33 degrees C which suggests the involvement of a phase transition rather than of an enzymatic activity of the toxin.

Animals↗
PubMed1979

The actions of tubocurarine at the frog neuromuscular junction.

1. The action of tubocurarine on voltage-clamped frog muscle end-plates has been re-examined by means (a) equilibrium dose-ratio measurements, (b) current fluctuation measurements and (c) voltage-jump relaxation measurements. 2. The equilibrium measurements can be interpreted as implying that tubocurarine has (a) a competitive blocking action, with a dissociation constant of 0.34 microM, which is not dependent on membrane potential, and (b) an additional voltage-dependent blocking action. 3. In the presence of tubocurarine two kinetic components can be seen. The faster one is similar to, but rather faster than, the normal ion channel closing rate. The other is much slower (1--3 sec), and, in relaxation experiments it is in the opposite direction to the fast relaxation. 4. A number of alternative explanations for the results are discussed. The mechanism that fits them best appears to be a combination of competitive block (or block of shut channels), with a strongly voltage-dependent block of open ion channels by tubocurarine. Estimates of the rate constants for channel blocking (and their voltage dependence) are derived. From these estimates the dissociation constant for the binding of tubocurarine to open channels appears to be roughly 0.12 microM at --70 mV and 0.02 microM at --12 mV. 5. Several potential sources of error in the experiments, and in their interpretation, are discussed. The most serious of these are problems associated with diffusion in the small volume of the synaptic cleft, viz. (a) changes in cleft concentration consequent on changes in binding, and (b) ionophoretic flux of antagonist and agonist into the synaptic cleft.

Animals↗
PubMed1978

Determination of dose-response curves by quantitative ionophoresis at the frog neuromuscular junction.

1. Quantitative ionophoresis at the neuromuscular junction is possible when (a) the drug is released from appropriate distances (15--20 micrometer for most drugs), (b) the topology of receptors is known and (c) high resistance drug pipettes (100--200 M omega) are sued. 2. With this method, drug concentration-endplate conductance relations were determined in voltage-clamped end-plates of the frog for the agonists ACh, carbamylcholine (CCh) and suberyldicholine (SubCh). 3. Based on the co-operative and independent model, theoretical dose-response curves were computed using as parameters the Hill coefficient nH, maximum conductance gmax., and apparent dissociation constant K. It was found that the co-operative model fitted the data much better than the independent model. 4. Based on the co-operative model, the mean maximum conductance for ACh was gmax. = 169 nS/micrometer, equivalent to 9000 ionic channels/micrometer length of a nerve terminal which can be opened at high drug concentrations. 5. The maximum conductance for CCh at--80 mV membrane potential was, on the average, 78% of that for ACh measured at the same end-plates. This value is termed the relative efficacy of CCh. 6. The mean values for the apparent dissociation constant K were 27.8 micrometer for ACh, 336 micrometer for CCh and 18 micrometer for SubCh. 7. The inhibition of the acetylcholinesterase activity by edrophonium (3--10 micrometer) affected only the local ACh concentration at the receptor sites, but not gmax. and nH. 8. Dose-response curves measured before and after removal of single nerve terminals in collagenase-treated muscle fibres showed no change in the nH, gmax. and K. A slight increase in gmax. to a value of 218 nS/micrometer observed comparing collagenase-treated and untreated end-plate. 9. Desensitization of receptors may occur in the range of several tens of milli-seconds.

Acetylcholine↗
PubMed1976

The M. omohyoideus of the mouse as a convenient mammalian muscle preparation. A study of junctional and extrajunctional acetylcholine receptors by noise analysis and cooperativity.

Muscles from cats, rats, guinea pigs and mice have been investigated as preparations for visualizing mammalian neuromuscular junctions with the aid of Nomarski interference optics. The M. omohyoideus of the mouse was found to be most convenient. Electrophysiological investigations showed that an endplate is normally surrounded by a population of perijunctional receptors. For junctional receptors in the endplate, a Hill coefficient of nH = 2.6 for acetylcholine was determined at 38 degrees C, decreasing to a value of 2.3 at room temperature. For both perijunctional and extrajunctional receptors (the latter occurring after denervation), the coefficient nH was 1.9. Noise analysis revealed a channel conductance gamma which changed abruptly from 22.4 +/- 1.0 pS (10--23 degrees C) to 45.6 +/- 3.9 pS (34--39 degrees C) in a very small temperature range around 25.5 degrees C. The mean channel lifetime tau was 0.3 ms at 39 degrees C and 1.0 ms at 23 degrees C.

Animals↗
PubMed1976

Junctional and extrajunctional acetylcholine receptors in normal and denervated frog muscle fibres. Noise analysis experiments with different agonists.

Ionic channel properties of acetylcholine receptors located in, in the vicinity of, or far away from a frog neuromuscular junction were investigated by noise analysis of drug induced current fluctuations. For drugs applied to the junction, in certain cases two Lorentzian curves were necessary to describe the data. It is postulated that the reason for this observation is that a contribution from perijunctional receptors was being observed. The conductance of a single channel in the junction was independent of the nature of the agonist and had an average value of 17.9 pS (temperature range 8-25 degrees C, solution buffered with Tris). After denervation for 21 days the conductance gamma was 7.5 pS at extrajunctional locations. In the close neighbourhood of the junction (peri-junctional receptors) values were found between 4 and 19 pS. The mean value of the open channel life-time tau in the endplate exposed to acetylcholine was 2.4 ms at 8-11 degrees C. This value was 0.90 ms with carbachol, 0.50 ms with succinylcholine, 0.28 ms with decamethonium and 0.45 ms with nicotine. The receptors outside the endplate exhibited tau-values which at a given temperature were 2-3 times larger than those at the endplate. Raising the temperature to 23 degrees C reduced all tau-values by factors of 2-3. It is concluded that at least two types of ACh-receptors with different properties exist in the muscle membrane, possibly produced by ACh-receptive units in different states of aggregation.

Acetylcholine↗
PubMed1976

Current-voltage relation and reversal potential at junctional and extrajunctional ACh-receptors of the frog neuromuscular junction.

The relationship between synaptic current and membrane potential has been examined at junctional and extrajunctional end-plate receptors of the frog. At junctional receptors, the synaptic current-membrane potential relationship is linear for close range iontophoretic ACh application and non-linear when it is delivered from some distance. At extra-junctional receptors the current-voltage relationship is always non-linear. These non-linearities can be related to the fact that in both cases [ACh] on membrane outlasts the mean life-time of the synaptic channels. When their mean life-time is varied, the current-voltage relationship obtained at junctional receptors is no longer linear and the peak synaptic conductance increases or decreases with hyperpolarization as the channel life time is shortened or lengthened, respectively.

Acetylcholine↗
PubMed1975

Acetylcholine receptor: modification of synaptic gating mechanism after treatment with a disulfide bond reducing agent.

Reduction of a 'reactive' disulfide bond in the postsyraptic membrane of the frog neuromuscular junction by dithiothreitol (DTT) decreases both the sensitivity of the membrane to applied acetylcholine (ACh) and the amplitude of the single 'shot effect'. Analysis of ACh induced conductance fluctuations in voltage clamped frog endplates indicates that DTT reduces both the amplitude gamma and duration tau of the elementary conductance events. The mean control value of gamma was 18.5-10(-12) omega-1 with no significant dependence on temperature. The mean control values pi were 2.3 msec at 7-9 degrees C and 0.94 msec at 20-22 degrees C. At 7-9 degrees C 1m7 DTT (20-50 min after application) reduced gamma to 61% of the control value and at 20-22 degrees C to 39%, while tau was reduced to 70% at both temperature ranges. The dose-response curve for iontophoretically applied ACh indicates that neither the total number of ionic channels nor the cooperativity within the receptors are changed. However, the affinity of ACh for the receptor sites was reduced. All effects of DTT were fully reversed by the oxidizing agent 5,5'-dithie-bis-(2-nitro-benzoic acid) (DTNB).

Acetylcholine↗