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Biomedical subjects

M E Eldefrawi

Publications and source records attributed to M E Eldefrawi.

At least 109 records · Page 6Linked to original sources
PubMed1979

Tetraethylammonium: voltage-dependent action on endplate conductance and inhibition of ligand binding to postsynaptic proteins.

Tetraethylammonium (Et(4)N(+)) ions depressed the amplitude and accelerated the decay rate of spontaneously occurring and nerve-evoked endplate currents (EPCs) in frog sartorius muscle. The relationship between peak EPC amplitude and membrane potential became nonlinear in the presence of 100 muM Et(4)N(+), and with drug concentrations of 250 muM or greater the current-voltage relationship exhibited negative conductance in the hyperpolarized region. Et(4)N(+) modified the exponential dependence of the EPC decay on membrane potential such that the decays between -150 and -50 mV were abbreviated and voltage independent but remained near control levels at more positive membrane potentials. The minimal effective concentration of Et(4)N(+) for altering the EPC time course was 10, and maximal effects were attained with 100 muM. Little additional shortening in the EPC decay phase was detected on raising the drug concentration to 1000 muM. Acetylcholine noise analysis revealed a voltage-dependent reduction in the mean channel open time, which was comparable in magnitude to the shortening in the EPC decay, and a depression of single-channel conductance. In concomitant biochemical studies, Et(4)N(+) was found to inhibit the binding of both [(3)H]acetylcholine and [(3)H]perhydrohistrionicotoxin to receptor-rich membranes from the electric organ of Torpedo ocellata with K(i) values of 200 muM and 280 muM, respectively. These results suggest that Et(4)N(+) interacts with both the acetylcholine receptor and its associated ionic channel. The voltage-dependent actions of Et(4)N(+) are attributed to blockade of the ionic channel in closed as well as open conformation.

Acetylcholine↗
PubMed1979

Biochemical studies on the ionic channel of Torpedo acetylcholine receptor.

1. [3H]H12-HTX binding to Torpedo electric organ membranes is saturable and inhibited by ligands that modulate EPCs. There is a small proportion of nonspecific binding to the membrane. 2. The validity of utilizing [3H]H12-HTX as a specific label for the ionic channel of the nicotinic receptor is extablished by the good correlation between the potency of HTX analogues in reducing EPC amplitudes and their inhibition of [3H]H12-HTX binding. 3. Receptor drugs and toxins inhibit [3H]ACh binding to the ACh receptor, but do not inhibit significantly [3h]h12-htx binding to the ionic channel at similar concentrations. 4. Various drugs and toxins with different modes of action modulate EPCs and inhibit [3H]H12-HTX binding to the ionic channel of the nicotinic receptor. Most such drugs and toxins, at similar concentrations, do not inhibit [3H]ACh binding to the ACh receptor, but some do, such as quinacrine and TEA. 5. The ionic channel of the nicotinic receptor is a protein which is solubilized by cholate and retains its affinity for H12-HTX as well as its drug sensitivity. 6. The ACh receptor is separated from its ionic channel, and different conditions affect the proportion of separated molecules.

Acetylcholine↗
PubMed1978

Acetylcholine receptor and ionic channel of Torpedo electroplax: binding of perhydrohistrionicotoxin to membrane and solubilized preparations.

The electric organ of the ray, Torpedo ocellata, can serve as a source for both the acetylcholine (ACh) receptor and its ionic channel. The two entities were identified by their specific binding of [3H]ACh and [3H]perhydrohistrionicotoxin ([3H]H12-HTX), respectively. Binding of [3H]H12-HTX was inhibited by certain drugs and toxins, e.g., histrionicotoxin (HTX), amantadine, and tetraethylammonium (TEA) ions at concentrations that did not inhibit [3H]ACh binding. However, the specific carbamoylcholine-induced 22Na efflux from microsacs from the electric organ membranes was blocked by inhibitors of either the receptor or its ionic channel. The ionic channel had the properties of a protein as judged by heat sensitivity and the inhibition of [3H]H12-HTX binding, after incubation of the electric organ membranes with protein reagents such as p-chloromercuribenzenesulfonic acid (PCMBS) or N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ). The "binding" of [3H]H12-HTX at 4 X 10(-8) M to lipids in the microsacs was 12% of the total binding to intact microsacs and was nonsaturable and insensitive to heat or specific drugs. After solubilization with cholate, the [3H]H12-HTX binding subunits retained the same affinities for toxins and drugs. The Kd for [3H]H12-HTX was 3 X 10(-7) M. The majority of the ionic channel could be separated from the ACh receptors in the cholate extract by incubation with ACh-receptor affinity gel and ACh-receptor antibodies. The ACh receptor purified by this affinity gel contained only a few active ionic channel units as judged by low levels of high affinity binding of [3H]H12-HTX. On the other hand, after solubilization with Triton X-100, all the ionic channel molecules were either separated or denatured so that the purified ACh receptor did not exhibit high affinity binding for [3H]H12-HTX.

Amphibian Venoms↗
PubMed1978

Amantadine: neuromuscular blockade by suppression of ionic conductance of the acetylcholine receptor.

Amantadine hydrochloride decreases the sensitivity of denervated mammalian muscle to iontophoretically applied acetylcholine. The drug depresses the amplitude of the end-plate current and reverses the slope of the relation between half-decay time and membrane potential suggesting that it alters the ionic conductance that is mediated by the acetylcholine receptor. Binding studies confirm that amantadine acts on the ion conductance modulator rather than the acetylcholine receptor.

Acetylcholine↗
PubMed1978

Experimental autoimmune myasthenia gravis: the rabbit as an animal model.

Rabbits immunized with acetylcholine (ACh) receptor purified from Torpedo electroplax were studied after they were paralyzed and exhibiting respiratory distress. Intercostal muscles from the immunized rabbits had reduced amplitude of miniature end-plate potentials (MEPPs) as well as reduced junctional ACh sensitivity. However, a large percentage of the cells studied (40%), which exhibited no MEPPs, had junctional ACh sensitivity that was 45% of normal. It is suggested that, unlike myasthenic patients, such paralyzed and dying rabbits may have, in addition to postsynaptic damage, neurons that are damaged or separated from the muscle. Serums from six paralyzed rabbits inhibited binding of [3H]ACh and [125I]alpha-bungarotoxin to Torpedo ACh-receptor to varying degrees: 18.8--95.5% and 42.5--86.1%, respectively. Immune serums also inhibited the carbamylcholine-induced 22Na efflux from Torpedo microsacs, but neither they nor the immunoglobulins inhibited neuromuscular transmission when applied to intercostal muscles from a control rabbit. The data suggest that homology between receptor and antibody is important for inhibition of ACh binding to its receptor and its function. The role of complement in pathogenesis is also discussed, and so is the relationship of the ACh-receptor to its ionic channel.

Animals↗
PubMed1977

Experimental autoimmune myasthenia gravis in rats. Modification by thymectomy and prednisolone.

In rats immunized with purified acetylcholine receptor protein (AChRP) from Torpedo electroplax, a defect of neuromuscular transmission physiologically identical to that seen in myasthenia gravis developed. The most sensitive index of the neuromuscular blockage was miniature end-plate potential (MEPP) amplitude. As early as 24 hours after inoculation with AChRP, the thymus showed reactive changes that are probably nonspecific. Removal of the thymus before or within three days after immunization delayed, but did not prevent, development of reduced MEPP amplitude. Prednisolone given within 35 days after immunization produced reversal of MEPP reduction within 24 hours, but had no such immediate effect when given 15 days later. It is probable that prednisolone acted by reducing the immunologic responsiveness of the animals during the developing phase of the defect of neuromuscular transmission.

Action Potentials↗