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S Ginsburg

Publications and source records attributed to S Ginsburg.

At least 19 recordsLinked to original sources
PubMed1992

A long closed state of the synaptosomal bursting potassium channel confers a statistical memory.

1. The statistical properties of the bursting potassium channel from fused Torpedo synaptosomes were studied by using patch-clamp recording and time series analysis. 2. Voltage steps produce channel openings; the number of channels opening fluctuates from trial to trial. The maximal current observed in each trial is strongly dependent on the previous history of the membrane patch. Trials with no activity are frequently clumped together and so are trials with intense activity. 3. Autocorrelation analysis reveals a strong interdependence of successive responses, which is voltage dependent. 4. We propose that the strong statistical interdependence of responses to successive depolarizing pulses (the statistical "memory") is a manifestation of a long lived closed state. We speculate that this statistical memory may be of significance in frequency modulation of transmitter release.

Animals↗
PubMed1991

A bursting potassium channel in isolated cholinergic synaptosomes of Torpedo electric organ.

1. Pinched-off cholinergic nerve terminals (synaptosomes) prepared from the electric organ of Torpedo ocelata were fused into large structures (greater than 20 microns) using dimethyl sulphoxide and polyethylene glycol 1500, as previously described for synaptic vesicles from the same organ. 2. The giant fused synaptosomes were easily amenable to the patch clamp technique and 293 seals with a resistance greater than 4 G omega were obtained in the 'cell-attached' configuration. In a large fraction of the experiments, an 'inside-out' patch configuration was achieved. 3. Several types of unitary ionic currents were observed. This study describes the most frequently observed single-channel activity which was found in 247 out of the 293 membrane patches (84.3%). 4. The single-channel current-voltage relation was linear between -60 and 20 mV and showed a slope conductance of 23.8 +/- 1.3 pS when the pipette contained 350-390 mM-Na+ and the bath facing the inside of the synaptosomal membrane contained 390 mM-K+. 5. From extrapolated reversal potential measurements, it was concluded that this channel has a large selectivity for K+ over Na+ (70.4 +/- 11.5, mean +/- S.E.M.). Chloride ions are not transported significantly through this potassium channel. 6. This potassium channel has a low probability of opening. The probability of being in the open state increases upon depolarization and reaches about 1% when the inside of the patch is 20 mV positive compared to the pipette side. 7. The mean channel open time increases with depolarization; thus the product current x time (= charge) also increases upon depolarization, showing properties of an outward rectifier. 8. The potassium channel in the giant synaptosome membrane has a bursting behaviour. Open-time distribution, closed-time distribution and a Poisson analysis indicate that the minimal kinetic scheme requires one open state and three closed states.

Animals↗
PubMed1990

Studies on new, centrally active and reversible acetylcholinesterase inhibitors.

We have synthesized the tertiary amines of pyridostigmine and neostigmine, 3-pyridinol dimethylcarbamate (norpyridostigmine) and 3-dimethylaminophenol dimethylcarbamate (norneostigmine) respectively, and we have tested their abilities to cross the blood-brain barrier and inhibit mouse brain AChE activity. The in vivo inhibition of AChE activity by norpyridostigmine reaches 72% at 10 minutes which is comparable to that seen with physostigmine (73% at 10 minutes). Inhibition by norneostigmine is less effective (50% at 10 minutes) and approaches that obtained with tetrahydroaminoacridine (57% at 10 minutes). These data show that both norpyridostigmine and norneostigmine cross the blood-brain barrier and that they are effective inhibitors of mouse brain AChE activity. These drugs could be useful in the treatment of memory impairment associated with Alzheimer's disease, and other memory disorders.

Acetylcholinesterase↗
PubMed1989

Ionic channels in synaptic vesicles: are they involved in transmitter release?

Synaptic vesicles were isolated from the nerve terminals of Torpedo electric organ. After fusion, 'giant' vesicles were formed which could be examined by the patch clamp technique. One of the cationic channels, the P channel, shows a small preference for K+ compared to Na+ and has multiple conductance levels. Its rate of opening is voltage and calcium dependent. Fractal analysis of the P channels reveals that its behaviour does not seem to be fractal in nature. At voltages where only one conductance level is observed, fractal analysis shows at least one discrete open state and at least two discrete closed states. There are considerable similarities between the P channel and channels found in granules from the hypophysis. These channels resemble, in turn, the channels found in gap junctions. Therefore, it is not unwarranted to speculate that a gap-junction-like communication between the secretory vesicle and the extracellular space may occur during exocytosis.

Animals↗
PubMed1989

Modulation of effect of extracellular calcium buffering in cardiac muscle.

The buffering of extracellular calcium by citrate, with identical free calcium levels in the buffered and unbuffered medium, was previously found to markedly reduce tension in frog and guinea pig atria. We now report the following results. 1) In guinea pig, postest contractions are not reduced by citrate. 2) In frog the negative inotropic effect of citrate is greatly attenuated by partially replacing extracellular sodium concentration ([Na+]o) with lithium or sucrose. In contrast, in low [Na+]o, sodium salts of weak acids (which cause intracellular acidosis) still reduce tension. These findings strongly support the suggestion that citrate does not reduce tension directly, e.g., by causing intracellular acidosis or by reducing voltage-dependent calcium currents. 3) Higher stimulation rates also decrease the effect of citrate. 4) Treatment with neuraminidase or phospholipase D, both of which alter sarcolemmal calcium binding, dose not change the effect of citrate. 5) The positive inotropic effect of strophanthidin is reversibly lost in the presence of citrate. Our results provide a different, novel approach to support earlier suggestions that the extracellular matrix and/or the sarcolemma contain abundant calcium-binding sites that supply some of the calcium for contraction. Citrate presumably binds calcium more strongly, thereby "trapping" calcium released from the extracellular "stores," so that less calcium is made available for contraction. The inotropic effect of cardiac glycosides may also depend on the calcium that is bound to these stores.

Animals↗
PubMed1987

Negative inotropic effect of extracellular calcium buffering in cardiac muscle.

Heart muscle contracts more vigorously when calcium levels are raised. A transient depletion of calcium from restricted extracellular spaces occurs with each contraction. We decided to maintain the concentration of this ion at a constant level by using an external calcium buffering system. It was found that buffering calcium at a millimolar level (using citrate as a buffer) caused a decrease, rather than an increase in the strength of contraction. The mean reduction in peak tension was by 27% in guinea pig and by 50.5% in frog atrium. This finding is analyzed; its most plausible explanation is the hypothesis that the buffer dissipates a calcium inhomogeneity, consisting of a higher calcium concentration adjacent to the membrane. Alternative interpretations such as intracellular acidosis, were tested experimentally and ruled out.

Animals↗
PubMed1978

Active transport of carnitine into skeletal muscle.

Skeletal muscle carnitine concentration exceeds plasma carnitine concentration. To determine whether this concentration gradient is maintained by active transport we studied rat soleus and extensor digitorum longus muscles. Observations consistent with the existence of an active transport mechanism were that the soleus accumulated carnitine linearly for 3 hours of incubation to exceed a distribution ratio of 1; the temperature coefficient for carnitine accumulation between 33 degrees C and 43 degrees C was 2.0; anaerobic incubation reduced carnitine accumulation by 30 percent; and the rate of carnitine accumulation was saturated at high substrate concentrations and competitively inhibited by gamma-butyrobetaine. The Km for carnitine of the carnitine transport mechanism of the soleus muscle was 0.259 mM and of the extensor digitorum longus muscle, 0.585 mM. The greater affinity of the soleus transport mechanism may explain the difference in carnitine transport by red and white muscle in intact animals. A defect in active transport of carnitine may be involved in the pathogenesis of some human myopathies characterized by excessive lipid storage and in diphtheritic cardiomyopathy.

Animals↗
PubMed1976

Use of current-voltage diagrams in locating peak energy barriers in cell membranes.

The current-voltage relations obtained by integrating the Nernst-Planck equations for a variety of energy profiles are obtained. A simple and approximate method for comparing these relations is described. The method is based on using a linearized transform of current-voltage relations for an Eyring single barrier model. A parameter, gamma, related to the location of the single barrier in the Eyring model, and to the shape of the barrier in other models, is readily obtained from the slopes of the linearized relations. It is then a simple matter to determine whether a given current-voltage relation allows discrimination between any particular energy profiles. The results show that the equivalent Eyring model does not always place the peak energy barrier in the same position as other models and that quite large errors in the assignment of position may be made if such a model is used. The results are also used to test the ability of some experimental current-voltage diagrams to discriminate between various energy profiles.

Biological Transport, Active↗
PubMed1975

Wound botulism.

Botulism occurring in patients with wounds has been thought of as a rare disease. A patient with a lacerating wound of his hand and wrist and an avulsion of his fourth finger developed diplopia, dizziness, and slurred speech one week later, followed by generalized weakness and difficulty in swallowing. Repetitive nerve stimulation studies showed signs of neuromuscular block consistent with the diagnosis of botulism. Results of bacteriologic and immunologic tests were not revealing, but the subsequent course of progressing, and retrogressing, bulbar signs and symptoms with eventual nearcomplete recovery confirmed the diagnosis. Increasing awareness and employment of electrophysiologic studies are uncovering increasing numbers of cases.

Adult↗
PubMed1971

Neuromuscular blocking activity of a new series of quaternary N-substituted choline esters.

1. The neuromuscular blocking activity of a new group of mono- and diquaternary N-substituted choline esters of several carboxylic acids has been evaluated in various whole animal preparations in the mouse, rat and cat.2. A basic non-depolarizing mechanism was present in all but one compound-a depolarizing agent, which was studied for comparison. There was evidence of facilitatory activity and nicotinic stimulation in the monoquaternary compounds. These effects were diminished in the diquaternary compounds.3. The presence of a bulky aromatic ring system on the nitrogen atom appeared to increase both neuromuscular blocking potency and facilitatory activity in the experimental animal. A similar relationship had previously been demonstrated in vitro in another study.4. The duration of action, although short in most compounds, did not correlate well with previously determined in vitro hydrolysis rates, possibly because of species differences.5. The general pharmacology of each compound appeared to depend considerably upon the structure of the choline moiety.

Animals↗
PubMedDate not supplied

Activation of protein kinase C augments evoked transmitter release.

In view of the emerging role of the phosphoinositide system in cellular communication we examined its involvement in quantal-transmitter release, which is a key element in synaptic transmission. Transmitter release is normally activated by an increase in intracellular calcium, achieved either by entry of calcium ions through the presynaptic membrane or by intracellular calcium liberation. One of the targets of the phosphoinositide signalling system is the enzyme protein kinase C (PKC), which can be activated experimentally by tumour promoting phorbol esters, including 12-O-tetradecanoylphorbol-13-acetate (TPA). Such activation of PKC may be implicated in transmitter release in two ways. First, phorbol esters were found to increase secretion and enhance calcium currents; it might therefore be expected that they would increase synaptic transmitter release. But phorbol esters also inhibit the calcium current in dorsal root ganglion neurones. We report that the phorbol ester TPA augments synaptic transmission at the neuromuscular junction by increasing transmitter liberation. Activation of PKC also depends synaptic depression.

Animals↗
PubMedDate not supplied

Potential clinical uses of short-acting nondepolarizing neuromuscular-blocking agents as predicted from animal experiments.

It is readily evident that a short-acting nondepolarizing agent suitable for clinical use would be of value in anesthesiology. The most commonly used short-acting relaxant, succinylcholine, is a depolarizing drug, with all the side effects inherent in such agents. The authors have investigated the actions of several short-acting nondepolarizing ester neuromuscular-blocking drug in comparison with succinylcholine, and theri interactions with d-tubocurarine, and inhibitors of true and plasma cholinesterase. Two experimental agents, HH-85 and JJ-142, are examples. Tests in animals suggest areas of extrapolation to human use.

Animals↗