Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The blocking effects of local anesthetics, mexiletine and disopyramide on the sodium currents (INa) of enzymatically isolated, single cells from rat ventricle were studied under voltage clamp conditions. A suction pipette technique was used for voltage clamp and internal perfusion. Potassium currents were blocked by replacing K+ with Cs+ in the internal and external solutions; calcium currents were blocked by replacing Ca2+ with Co2+ in the external solution to isolate INa. When the cells were stimulated infrequently (less than 1 Hz), both drugs produced dose-dependent depression of INa, which was correlated with one-to-one binding to sodium channel. A half-blocking concentration (KD) of 2.8 X 10(-5) M was observed for both agents. The shape of the current-voltage curve along the voltage axis remained unchanged in the presence of either drug. Both drugs shifted the inactivation curve of INa to more negative potentials. Mexiletine produced a marked use-dependent blockage of INa, whereas disopyramide did not produce significant use-dependent block under similar experimental conditions. Both drugs prolonged the recovery of INa from inactivation. The results suggested that both drugs interact with the inactivation mechanism of the sodium channels of rat myocardial cells.
J Mol Cell Cardiol 1985 May
PMID:Blockage of the sodium current in isolated single cells from rat ventricle with mexiletine and disopyramide. 241 42

Goniopora toxin (GPT), a polypeptide toxin of 9700 Da isolated from coral, markedly slows inactivation of sodium currents recorded under voltage clamp in mouse neuroblastoma cells. The voltage dependence of sodium channel activation is shifted to more negative membrane potentials by 9.8 +/- 2.1 mV, and the voltage dependence of channel inactivation is shifted to more positive membrane potential by 6.0 +/- 2.5 mV. These actions of GPT are voltage dependent with an e-fold increase in K0.5 for toxin action for each 48.3-mV depolarization between -80 and +40 mV. GPT requires Na+ or another alkali metal cation in the extracellular medium for its effect on sodium channels. The relative effectiveness of the different cations tested is Na+ greater than K+ greater than Rb+ greater than Li+ greater than Cs+ much greater than choline+. Like other polypeptide neurotoxins that slow inactivation of sodium channels, GPT enhances persistent activation of sodium channels by veratridine. However, GPT does not block the binding of 125I-labeled Leiurus scorpion toxin to neurotoxin receptor site 3 on sodium channels at concentrations which effectively slow channel inactivation. Therefore, our results define a new site on the sodium channel at which specific effects on inactivation can occur.
Mol Pharmacol 1986 Apr
PMID:Mechanism of action of a polypeptide neurotoxin from the coral Goniopora on sodium channels in mouse neuroblastoma cells. 242 33

Tottering mice, in which a single gene lesion leads to prolonged hyperexcitability and spontaneous epilepsy, were studied to determine whether enhanced electrical activity leads to down regulation of sodium channels in central neurons. The number of sodium channels in synaptosomes, as assessed by saxitoxin binding, was decreased from 5.38 +/- 0.06 pmol/mg protein in coisogenic controls to 3.85 +/- 0.10 pmol/mg protein (P less than 0.001) in tottering mice without a change in the KD for saxitoxin. Neurotoxin-activated 22Na+ influx per sodium channel was increased 80% in tottering mice (P less than 0.001). Evidently, the increased level of electrical excitability characteristic of the tottering phenotype causes down regulation of the sodium-channel number and alteration of channel function in the nerve terminals of central neurons.
Cell Mol Neurobiol 1986 Jun
PMID:Down regulation of sodium channels in nerve terminals of spontaneously epileptic mice. 242 71

In isolated heart preparations, dl-verapamil inhibits the increased vulnerability to ventricular fibrillation and reduces myocardial tissue levels of cyclic 3'5'-adenosine monophosphate (cyclic AMP), a proposed arrhythmogenic agent. The ventricular antiarrhythmic effect of dl-verapamil may not be mediated by selective slow channel inhibition since both d(+) and l(-) isomers display equipotent activity. Three different mechanisms may contribute to the antiarrhythmic properties of dl-verapamil: calcium channel antagonism (l(-) isomer), sodium channel inhibition (d(+) isomer) and reduced cyclic AMP accumulation. In the intact animal model, coronary artery ligation is associated with increased levels of circulating catecholamines and sympathetic neural overactivity. In isolated heart preparations, it is therefore appropriate to evaluate the influence of dl-verapamil and isomers on vulnerability to ventricular fibrillation and cyclic AMP accumulation during acute myocardial ischemia with added adrenergic stimulation. We found that dl and l(-) but not d(+)-verapamil (all 1.5 X 10(-7) M) inhibited the fall in ventricular fibrillation threshold through a mechanism not involving cyclic AMP. L(-) but not d(+) verapamil inhibited Ca2+ dependent slow responses and decreased action potential duration at 90% repolarization. We propose that the ventricular antiarrhythmic property of dl and l(-) verapamil during acute regional myocardial ischemia with added adrenergic stimulation is due to inhibition of transsarcolemmal calcium influx.
J Mol Cell Cardiol 1986 Jun
PMID:The influence of verapamil and its isomers on vulnerability to ventricular fibrillation during acute myocardial ischemia and adrenergic stimulation in isolated rat heart. 242 59

The polyether lipid-soluble toxins isolated from the marine dinoflagellate Ptychodiscus brevis (formerly Gymnodinium breve) have been determined to bind to a unique site associated with rat brain synaptosomes. Using [3H]brevetoxin PbTx-3 as a specific probe, binding was determined at 4 degrees in rat brain synaptosomes using a rapid centrifugation technique. Rosenthal analysis yields a KD of 2.9 nM and a Bmax of 6.8 pmol of toxin/mg of protein. Labeled probe can be displaced by unlabeled PbTx-3, PbTx-2, or synthetic PbTx-3 (reduced PbTx-2) but not by a nontoxic, synthetic oxidized derivative of PbTx-2. Competition experiments using natural toxin probes specific for sites 1-4 of the voltage-dependent sodium channel have illustrated that PbTx-3 does not bind to any of the previously described sites associated with the channel. A fifth site is proposed. In addition, because of the varied nomenclature associated with the brevetoxins, a new classification system is proposed.
Mol Pharmacol 1986 Aug
PMID:Brevetoxins, unique activators of voltage-sensitive sodium channels, bind to specific sites in rat brain synaptosomes. 242 67

Radiolabeled neurotoxins have been used to study the structure and function of sodium channels. We studied the binding of [3H] batrachotoxinin A 20 alpha-benzoate [( 3H]BTX-B) to specific sites on sodium channels on rat cardiac myocytes. Calcium-tolerant myocytes were prepared by collagenase dispersion of adult rat hearts and were 75-83% viable. As with the nerve channel, specific binding of [3H]BTX-B to its receptor site was seen only in the presence of sea anemone toxin (ATX). The affinity of ATX for its binding sites may be estimated from its concentration-dependent stimulatory effect on [3H]BTX-B binding. These results suggest that, in the presence of 5.4 mM KCl, the myocytes have two affinities for ATX with estimated dissociation constants of 0.52 microM and 12.9 microM. Depolarization of the myocytes with either 65 mM KCl or 0.1 mM BaCl2 results in the loss of the 0.52 microM component, suggesting that it is voltage sensitive. The 0.52 microM and 12.9 microM components have maximal binding capacities corresponding to 4 and 11 sites/micron 2 of myocyte surface area, respectively. Scatchard analysis of [3H]BTX-B binding in the presence of ATX demonstrates a single class of sites with a KD of 25-35 nM. These results demonstrate that [3H]BTX-B can be used as a radioligand probe of the adult rat sodium channel and will facilitate a biochemical approach to the study of the interaction between antiarrhythmic drugs and the sodium channel.
Mol Pharmacol 1986 Dec
PMID:Binding of [3H]batrachotoxinin A benzoate to specific sites on rat cardiac sodium channels. 243 Dec 64

The inhibitory effect of disopyramide, quinidine, mexiletine, lidocaine, tocainide and aprindine on the maximum upstroke velocity (Vmax) of action potential was examined in isolated guinea-pig cardiac muscles in terms of their sodium channel block during activated and/or inactivated state. In right ventricular papillary muscles, a conditioning clamp pulse was applied from the resting potential to 0 mV level using the single sucrose-gap voltage clamp technique, and Vmax of test action potential elicited 100 ms after termination of the clamp pulse was measured as an index of sodium channel availability. Such clamp pulses caused various Vmax decreases in the presence of the six drugs. The decrease in Vmax by 10 ms clamp pulse was defined as the activated channel block (ACB), and the decrease in Vmax as the clamp pulse duration was prolonged from 10 to 500 ms was defined as the inactivated channel block (ICB). The ratio of ICB to ACB was less than 1.0 (0.36-0.51) for disopyramide and quinidine, and much greater than 1.0 (2.61-11.23) for mexiletine, lidocaine, tocainide and aprindine. From these findings it was suggested that the former group of drugs may block the sodium channel mainly during the upstroke phase of action potential, while the latter do so mainly during the plateau phase. This assumption was confirmed by experiments comparing the potency of Vmax inhibition in atrial and ventricular muscles isolated from the same guinea-pig heart.
J Mol Cell Cardiol 1987 Apr
PMID:Block of activated and inactivated sodium channels by class-I antiarrhythmic drugs studied by using the maximum upstroke velocity (Vmax) of action potential in guinea-pig cardiac muscles. 244 Oct 73

Agents that increase intracellular concentrations of Na+ stimulate phosphoinositide breakdown in guinea pig cerebral cortical synaptoneurosomes. When combined, these agents did not have additive effects on phosphoinositide breakdown but did have additive or greater than additive effects with carbamylcholine. Scorpion venom (Leiurus quinquestriatus) and pumiliotoxin B, which induce small increases in influx of 22Na+ in synaptoneurosomes, stimulate phosphoinositide breakdown by about 6- and 3-fold, respectively; both effects are inhibited by tetrodotoxin (TTX). Batrachotoxin (BTX) and veratridine, which cause a large increase in influx of 22Na+ through activation of voltage-dependent sodium channels, induce a 5- to 6-fold dose-dependent increase in phosphoinositide breakdown, which appears competitively inhibited by 5 microM TTX. BTX- and veratridine-elicited influx of 22Na+ into synaptoneurosomes is virtually completely blocked by 5 microM TTX. Agents that block voltage-dependent calcium channels, such as D-600, nifedipine, and Co2+, do not inhibit either influx of 22Na+ or stimulation of phosphoinositide breakdown elicited by scorpion venom, pumiliotoxin B, or BTX. Cadmium ions (200 microM), which are known to block TTX-resistant sodium channels, block phosphoinositide breakdown induced by agents that activate sodium influx through sodium channels. Cadmium blocks BTX-induced phosphoinositide breakdown with an IC50 value of 48 microM, while blocking BTX-induced 22Na+ influx in synaptoneurosomes with a 13-fold lower potency (IC50, 610 microM). In the presence of 0.5 microM TTX, the IC50 for Cd2+ inhibition of BTX-induced 22Na+ influx is now 430 microM. Neither TTX nor Cd2+ antagonize neurotransmitter- or monensin-induced phosphoinositide breakdown. It appears that BTX-induced phosphoinositide breakdown in guinea pig synaptoneurosomes is dependent primarily on activation of TTX-resistant, Cd2+-sensitive sodium channels that account for only a small fraction of the total sodium influx induced by BTX in synaptoneurosomes. However, cadmium also may in some way inhibit phosphoinositide breakdown elicited by sodium channel agents at a point subsequent to sodium influx.
Mol Pharmacol 1987 Oct
PMID:Stimulation of phosphoinositide breakdown in brain synaptoneurosomes by agents that activate sodium influx: antagonism by tetrodotoxin, saxitoxin, and cadmium. 244 71

The effects of a polypeptide toxin of 25,000 Da from the marine snail Conus striatus (CsTx) on sodium channels in mouse neuroblastoma cells and rat brain synaptosomes were studied. CsTx slowed sodium channel inactivation without altering the time course of activation of the channels. The voltage dependence of sodium channel inactivation was shifted to more negative membrane potentials and made less steep. Peak sodium currents were increased, and the voltage dependence of activation was shifted to more negative membrane potentials. The action of the toxin was voltage-dependent. Maximum toxin effects were observed at membrane potentials in the range of -100 to -60 mV. Apparent KD values were calculated assuming a one-to-one binding interaction. At more positive membrane potentials, the apparent KD for toxin action increased e-fold for each 19-mV depolarization. Apparent KD also increased at membrane potentials more negative than -100 mV. CsTx did not have significant effects on the binding of saxitoxin or Leiurus alpha-scorpion toxin to their receptor sites on sodium channels. CsTx enhanced the binding of batrachotoxinin A 20-alpha-benzoate to sodium channels in the same concentration range as its physiological effects. It is concluded that CsTx interacts with a new receptor site on the extracellular surface of the sodium channel at which specific effects on channel inactivation can occur.
Mol Pharmacol 1987 Nov
PMID:Actions of a polypeptide toxin from the marine snail Conus striatus on voltage-sensitive sodium channels. 244 15

The possible presence of multiple sodium channel subtypes in bullfrog skeletal muscle was investigated in binding experiments with [3H]saxitoxin and in single-channel studies using planar lipid bilayers. Two classes of [3H]saxitoxin-binding sites were identified in membrane preparations. One class displayed a toxin specificity characteristic of voltage-dependent sodium channels: high affinity for saxitoxin (KD approximately equal to 0.5 nM), neosaxitoxin (KD approximately equal to 0.1 nM), and tetrodotoxin (KD approximately equal to 1.3 nM). A second class of membrane-associated binding sites exhibited high affinity for saxitoxin (KD approximately equal to 0.1 nM), lower affinity for neosaxitoxin (KD approximately equal to 25 nM), and complete insensitivity to tetrodotoxin at concentrations up to 32 microM. The first class corresponded to functional tetrodotoxin-sensitive sodium channels that could be incorporated and observed in planar bilayers in the presence of batrachotoxin. Similar attempts to incorporate tetrodotoxin-insensitive sodium channels from bullfrog muscle and heart membranes were unsuccessful. The unusual, tetrodotoxin-insensitive binding activity for [3H]saxitoxin was also found at nM levels in the high speed supernatant of homogenized skeletal muscle without the addition of detergents. This soluble class of sites exhibited low affinity for neosaxitoxin (KD approximately equal to 60 nM) and a very slow dissociation rate of [3H]saxitoxin (t0.5 approximately equal to 90 min), properties nearly identical to those of the tetrodotoxin-insensitive sites in membranes. The soluble saxitoxin-binding activity is also characterized by a more basic pH dependence and a complete lack of binding competition between saxitoxin and alkali cations. Bullfrog muscle appears to be a good tissue source for the purification of this soluble saxitoxin-binding protein.
Mol Pharmacol 1988 Feb
PMID:Multiple saxitoxin-binding sites in bullfrog muscle: tetrodotoxin-sensitive sodium channels and tetrodotoxin-insensitive sites of unknown function. 244 1


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>