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Biomedical subjects

M E Eldefrawi

Publications and source records attributed to M E Eldefrawi.

At least 91 records · Page 5Linked to original sources
PubMed1981

Regulation of [3H]perhydrohistrionicotoxin binding to Torpedo ocellata electroplax by effectors of the acetylcholine receptor.

The specific binding of [3H]perhydrohistrionicotoxin ([3H]H12-HTX) to the ionic channel of the nicotinic receptor in membranes from the electric organ of the electric ray Torpedo ocellata was studied by use of a rapid filter assay. The time course of the binding was monitored and the initial rate of binding (i.e. within 30 s) was found to be increased up to several hundredfold by the presence of several receptor agonists in a dose-dependent manner. Receptor antagonists blocked this agonist-increased initial rate of binding. The presence of receptor antagonists, with the exception of alpha-bungarotoxin, also increased the initial rate of [3H]H12-HTX binding, though to a much lesser degree than agonists. Preincubation of the membranes with carbamylcholine reduced the initial rate of binding in a time-dependent manner. This was proposed to be due to receptor desensitization. Thus, it is suggested that the time course of [3H]H12-HTX binding to the ionic channel sites is influenced by the conformational state of the receptor-channel complex such that receptor activation, inactivation, and desensitization appear to be reflected in [3H]H12-HTX binding.

Amphibian Venoms↗
PubMed1981

Recent advances in the molecular mechanisms of human and animal models of myasthenia gravis.

The receptor-channel molecule is a dynamic system which exists in multiple conformations and that is the way we should think of it when we study antibody interaction with the molecule. The results presented here suggest that some antibodies may affect receptor function by occupying sites other than the receptor site. Some of these sites may by exposed only in certain conformations, and occupation of some site by antibodies may effect conformational changes. These small but perhaps important differences in cholinergic channel properties of the myasthenic muscle from the normal one are revealed by studying the effect of myasthenic sera on drug interactions with the channel sites. The sera of myasthenics are able to react with certain channel conformations and are able to affect the interaction of channel antagonists such as H12HTX and QNB. The sera appear to act preferentially with the open conformation of the channel. As a consequence of such an effect, important conformational changes of the channel may fail to occur upon activation.

Acetylcholine↗
PubMed1981

Characterization of the electrogenic sodium channel from rat brain membranes using neurotoxin-dependent 22Na uptake.

The sodium channel was studied in osmotically-sensitive membrane preparations from rat brain and in innervated and chronically denervated rat soleus and extensor digitorum longus muscles. These experiments were undertaken in order to define a set of parameters for sodium channel function at the subcellular level to be used as a measure of retention of channel integrity upon subsequent isolation of the channel. Various neurotoxins and drugs were employed to control the permeability of the brain membranes to 22Na and the sodium-conductance properties of the muscles. Batrachotoxin (ED50 = 0.2 micrometer), veratridine (ED50 = 1 micrometer), or grayanotoxin I (ED50 = 30 micrometers) stimulated 22Na uptake in brain membranes is inhibited in an apparently uncompetitive manner by the sodium channel blocking agents tetrodotoxin and saxitoxin in a simple competitive manner by Ca2+ and in a partial or allosteric competitive manner by lidocaine and procaine. This 22Na uptake assay, which can be equated to a measure of equilibrium toxin binding, shows dependence on the concentration of the membranes and is sensitive to pH, temperature, ionic strength, and the ionic composition of the media. Parallel biophysical studies on sodium channels in rat muscle show that the properties of the sodium channel are similarly affected by these agents.

Action Potentials↗
PubMed1980

[3H]Phencyclidine: a probe for the ionic channel of the nicotinic receptor.

To evaluate [3H]phencyclidine ([3H]PCP)as a probe for the ionic channel of the nicotinic receptor, the characteristics of its binding to electric organ membranes od Torpedo ocellata and its effects on frog sartorius muscle were studied. Similar to PCP, [3H]PCP depressed the peak amplitude of endplate current, caused nonlinearity in the voltage-current relationship at negative potentials, accelerated the decay time of the end-plate current, and shortened the channel lifetime. Thus, [3H]PCP interacted with the ionic channel of the nicotinic receptor, although there were a few differences between its effect and that of PCP. Binding of [3H]PCP to Torpedo membranes was to sites on the ionic channel of acetylcholine (AcCho) receptor because it was saturable, dependent upon protein concentration, and inhibited by drugs that interact with the ionic channel, and the initial rate of binding was potentiated by receptor agonists. Equilibrium binding of [3H]PCP to Torpedo membranes was with two affinities, but in the presence of AcCho, [3H]PCP binding was with a single affinity. The affinities of channel drugs obtained by inhibition of binding of [3H]PCP and [3H[perhydrohistrionicotoxin to Torpedo membranes were different, with correlation coefficients of 0.52 and 0.82 in the absence and presence of a receptor agonist, respectively; this suggests differences in their binding sites on the ionic channel of the AcCho receptor.

Animals↗
PubMed1980

Phencyclidine interactions with the ionic channel of the acetylcholine receptor and electrogenic membrane.

The effects of phencyclidine (PCP) were studied on the electrogenic and chemosensitive properties of the neuromuscular junction of skeletal muscle as well as on the binding sites on the acetylcholine (AcCho) receptor and its ionic channel in the electric organ membranes of the electric ray. The directly elicited muscle twitch was markedly potentiated by prolonging the falling phase of the muscle action potential and blocking delayed rectification. The indirectly elicited muscle twitch was transiently potentiated and then blocked by PCP at concentrations below 60 muM. PCP blocked miniature endplate potentials and AcCho sensitivities at the junctional region of innervated muscle, blocked the extrajunctional sensitivity of the chronically denervated muscle, and significantly depressed the peak amplitude of the endplate current (EPC) in a voltage- and time-dependent manner. PCP also caused acceleration of the time course of EPC decay and shortening of the mean life-time of the open ionic channel. The effects of PCP were not due to inhibition of AcCho receptor sites because PCP did not protect against the quasi-irreversible inhibition of receptor sites by alpha-bungarotoxin, nor did it inhibit binding of [(3)H]AcCho or [(125)I-labeled alpha-bungarotoxin to the receptor sites. On the other hand, PCP blocked the binding of [(3)H]perhydrohistrionicotoxin to the sites of the ionic channel of the AcCho receptor. The data suggest that PCP reacts with the electrogenic K(+) channel and the ionic channel associated with the AcCho receptor in the open as well as the closed conformation.

Action Potentials↗
PubMed1980

Activation, inactivation, and desensitization of acetylcholine receptor channel complex detected by binding of perhydrohistrionicotoxin.

The effects of receptor activation were studied on the interaction of perhydrohistrionicotoxin (H(12)-HTX) with the ionic channel of the nicotinic acetylcholine (AcCho) receptor in membranes from the electric organ of Torpedo ocellata and with the endplate region of the soleus muscle of the rat. In Torpedo membranes, the initial rate (i.e., within 30 sec) of [(3)H]H(12)-HTX bindings to the ionic channel of the AcCho receptor was accelerated 10(2)- to 10(3)-fold in the presence of carbamoylcholine (Carb). H(12)-HTX also inhibited Carb-activated (22)Na(+) influx, over 95% inhibition at 10 muM H(12)-HTX. At this concentration H(12)-HTX did not inhibit [(3)H]AcCho binding to the AcCho-receptor sites. There was good correspondence between the degree of acceleration of [(3)H]H(12)-HTX binding and the stimulation of (22)Na(+) influx over a wide range of Carb concentrations (up to 100 muM). Preincubation of Torpedo membranes with Carb decreased the initial rate of [(3)H]H(12)-HTX binding, as well as the rate of (22)Na(+) influx, which may reflect desensitization of the AcCho-receptor. d-Tubocurarine inhibited the agonist-mediated acceleration of [(3)H]H(12)-HTX binding and (22)Na(+) influx. In the soleus muscle endplate, H(12)-HTX inhibited the transient depolarization induced by microiontophoretic application of AcCho; the more receptors activated and channels opened, the stronger was the inhibition by H(12)-HTX. These findings suggest that H(12)-HTX binds to closed and open ionic channels, with a preference for the latter conformation. It is also suggested that the conformational changes associated with activation or desensitization of the receptor can be monitored by studying binding of [(3)H]H(12)-HTX to the ionic channel sites as well as by the AcCho-receptor-regulated (22)Na(+) influx.

Acetylcholine↗