Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.4.3 (phospholipase C)
 18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cocaine can induce lethal cardiovascular events, including myocardial infarction and ventricular fibrillation. The mechanisms responsible for these cardiotoxic effects of cocaine remain largely to be determined. Cocaine has both sympathomimetic (inhibition of neuronal uptake of norepinephrine) and local anesthetic (Na+ channel blockade) properties. Neurotransmitters released from cardiac sympathetic nerves bind to both alpha- and beta-adrenergic receptors eliciting a cascade of intracellular responses. Stimulation of beta-adrenergic receptors activates adenylate cyclase, increasing cyclic AMP levels, whereas alpha-adrenergic receptor stimulation activates phospholipase C, increasing inositol trisphosphate. These second messengers, in turn, elicit increases in cystolic calcium. Elevations in cystolic calcium can provoke oscillatory depolarizations of the cardiac membrane, triggering sustained action potential generation and extrasystoles. Cocaine also acts as a local anesthetic by inhibiting sodium influx into cardiac cells, which impairs impulse conduction and creates an ideal substrate for reentrant circuits. Thus, the adrenergic and anesthetic properties of cocaine could act synergistically to elicit and maintain ventricular fibrillation. Adrenergic receptor activation would trigger the event whereas sodium channel blockade would create the reentrant substrate to perpetuate the malignant arrhythmias.
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PMID:Mechanisms responsible for the cardiotoxic effects of cocaine. 218 73

The sodium channel activators veratridine and batrachotoxin, the sodium ionophore gramicidin, and the calcium ionophore ionomycin stimulated phosphoinositide breakdown, as indicated by the increased accumulation of [3H]inositol monophosphate in embryonic chick heart cells. The levels of [3H]inositol trisphosphate and [3H]inositol bisphosphate were also increased by veratridine, indicating that there was increased hydrolysis of phosphatidylinositol bisphosphate by phospholipase C. The response to veratridine required both extracellular sodium and calcium, suggesting that calcium entry via Na/Ca exchange might activate phospholipase C. Fluorescence measurements with fura-2 confirmed that the sodium agents greatly increased the cytoplasmic calcium concentration. Veratridine (100 microM) increased cytoplasmic calcium from 94 +/- 4 nM to 862 +/- 103 nM, giving a maximal calcium increase in about 2 min. Batrachotoxin (1 microM) induced an even greater increase in calcium but required a longer time. Gramicidin also induced a large increase in cytoplasmic calcium which was maximal within 0.5 min. To directly test the calcium dependency of phospholipase C, we permeabilized the chick heart cells with saponin and monitored the production of inositol phosphates at different calcium concentrations. Raising the calcium concentration from 3 to 1000 nM increased the accumulation of [3H]inositol phosphates by nearly 4-fold with a half-maximal effect at about 200 nM calcium. The guanine nucleotide guanosine-5'-O-(3-thio)triphosphate (GTP gamma S) also stimulated accumulation of the InsPs and the response to (GTP gamma S) was potentiated by increasing the calcium concentration. The data suggest that the effect of the sodium agents on phosphoinositide hydrolysis results from an elevation of intracellular calcium which increases GTP-dependent phospholipase C activity. Thus, drugs or other conditions that elevate cytoplasmic calcium in heart cells may increase the hydrolysis of membrane phosphoinositides.
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PMID:Elevation of cytoplasmic calcium concentration stimulates hydrolysis of phosphatidylinositol bisphosphate in chick heart cells: effect of sodium channel activators. 245 Nov 16

Carbachol, a muscarinic receptor agonist and the sodium channel-activating agents, scorpion venom, veratridine, batrachotoxin and aconitine, were shown to stimulate the formation of [3H]inositol phosphates in [3H]inositol-labelled miniprisms, obtained from the cerebral cortex of the mouse. The inositol response to the Na+ channel-activating agents was inhibited by the sodium channel blocker tetrodotoxin (TTX), while the response induced by carbachol was partially resistant to TTX. The response to scorpion venom and the TTX-insensitive portion of the response to carbachol was additive, indicating different mechanisms. The presence of high potassium (K+) induced hydrolysis of inositide in a TTX-insensitive manner and was not additive with that resulting from sodium channel activators, thus indicating a common mechanism. The addition of large concentrations of magnesium to block the release of acetylcholine, did not inhibit the inositol response to high K+ or to veratridine. Calcium channel blockers such as nickel or cobalt, or the dihydropyridine calcium (Ca2+) channel activator BAY K 8644 and the calcium channel blocker nifedipine, nimodipine or PN-200 110 had little effect. Monensin, a sodium ionophore, stimulated the turnover of phosphatidylinositol at non-depolarizing concentrations and the omission of Na+ ions inhibited the response to sodium channel agents and to high K+. Thus, membrane potential and gradients of K+, Na+ and Ca2+ are all important factors determining the final effect on the turnover of phosphatidylinositol. The data are consistent with a model in which all these factors impinge on the Na+/Ca2+ exchanger regulating internal Ca2+ that, in turn, activates phospholipase C.
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PMID:Phosphoinositide hydrolysis induced by depolarization and sodium channel activation in mouse cerebrocortical slices. 255 Aug 41

Local anesthetics inhibited the sodium influx and the inositol phosphate accumulation elicited by the sodium channel activator batrachotoxin in guinea pig cortical synaptoneurosomes. Inhibitory effects of local anesthetics on sodium influx correlated with inhibitory effects on binding of a tritiated batrachotoxin analog to sodium channels in synaptoneurosomes. There was also a correlation between inhibitory effects on sodium influx and on inositol phosphate accumulation; most local anesthetics inhibited sodium influx at concentrations similar to those required for inhibition of inositol phosphate accumulation. Indeed, euprocin, bupivacaine, lidocaine, and certain analogs were nearly equipotent with respect to inhibition of sodium influx and inositol phosphate accumulation. Local anesthetics also inhibited inositol phosphate accumulation that was induced by carbamylcholine through both a tetrodotoxin-sensitive and tetrodotoxin-insensitive pathway. Certain local anesthetics, such as dibucaine, inhibited the tetrodotoxin-sensitive pathway with higher potency than for the tetrodotoxin-insensitive pathway, while others, such as quinacrine, inhibited tetrodotoxin-sensitive and tetrodotoxin-insensitive pathways with equal potency. Diphenhydramine and chlorpromazine appeared to inhibit carbamylcholine-elicited phosphoinositide breakdown through blockade of muscarinic cholinergic receptors rather than because of local anesthetic activity of inhibitory effects on phospholipase C.
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PMID:Local anesthetics: comparison of effects on batrachotoxin-elicited sodium flux and phosphoinositide breakdown in guinea pig cerebral cortical synaptoneurosomes. 284 89

The saxitoxin-binding component of the excitable membrane sodium channel exhibits glycoprotein characteristics as evidenced by its specific interaction with various agarose-immobilized lectins. The detergent-solubilized saxitoxin-binding component interacts quantitatively with immobilized wheat germ agglutinin and concanavalin A and fractionally with immobilized Lens culinaris hemagglutinin and Ricinus communis agglutinin. These lectins preferentially bind N-acetylglucosamine and sialic acid (wheat germ agglutinin), mannose (concanavalin A and Lens cunilaris) and galactose (Ricinus communis). Removal of terminal sialic acid residues by neuraminidase markedly decreases binding to immobilized wheat germ agglutinin but uncovers sites capable of interacting with lectins specific for galactose and N-acetylgalactosamine. beta-N-acetylglucosaminidase, an exoglycosidase, has no effect on the binding of the channel protein to wheat germ agglutinin. Similarly, phospholipase C has no effect on binding of the solubilized toxin binding component to this lectin. Neither wheat germ agglutinin nor concanavalin A free in solution alters the number of toxin binding sites or their affinity for toxin. The sodium channel saxitoxin-binding component to wheat germ agglutinin. Similarly, phospholipase C has no effect on binding of the solubilized toxin binding component to this lectin. Neither wheat germ agglutinin nor concanavalin A free in solution alters the number of toxin binding sites or their affinity for toxin. The sodium channel saxitoxin-binding component to wheat germ agglutinin. Similarly, phospholipase C has no effect on binding of the solubilized toxin binding component to this lectin. Neither wheat germ agglutinin nor concanavalin A free in solution alters the number of toxin binding sites or their affinity for toxin. The sodium channel saxitoxin-binding component appears to be a glycoprotein containing terminal sialic acid residues and internal mannose, galactose, N-acetylglucosamine, and N-acetylgalactosamine residues. The toxin binding site is spatially separated from the binding sites for the lectins studied. The effect of these sugar moieties must be considered when evaluating the biophysical parameters of the sodium channel.
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PMID:Glycoprotein characteristics of the sodium channel saxitoxin-binding component from mammalian sarcolemma. 626 57

Azido nitrophenylaminoacetyl [125I]iodo derivative of toxin II from Centruroides suffusus suffusus, a beta-toxin, and azido nitrophenylaminoacetyl [125I]iodo derivative of toxin V from Leiurus quinquestriatus quinquestriatus, an alpha-toxin, have been covalently linked after binding to their receptor sites that are related to the voltage sensitive sodium channel present in rat brain synaptosomes. Both derivatives labeled two polypeptides of 253000 +/- 20000 and 35000 +/- 2000 mol. wt. Labeling was blocked for each derivative by a large excess of the corresponding native toxin but no cross inhibition was obtained. These results suggest that both alpha - and beta - scorpion toxin receptors are located on or near the same two membrane polypeptides which may be part of the voltage dependent sodium channel.
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PMID:Photoaffinity labeling of alpha- and beta- scorpion toxin receptors associated with rat brain sodium channel. 631 78

alpha-Scorpion toxin binding to its receptor--one component of the voltage-sensitive sodium channel--was studied in an attempt to define its phenotypic specificity. To this end we investigated the ability of neuronal, glial myogenic and fibroblastic cell lines to bind alpha-toxin II, purified from venom of the scorpion Androctonus australis Hector. A single class of saturable high-affinity (Kd congruent to 1 nM) binding sites, was present only in cell lines exhibiting some of the characteristics of normal neuronal cells, such as the N18, NIE-115, NS20, BN10-10, NG108-15 and T28 cell lines. NIA-103, which is an electrically non-excitable neuronal cell, gave negative results. In glial (G26-20, TR6B, C6) myogenic (T984) or fibroblastic (L) cell lines, we were unable to detect high-affinity binding sites for alpha-scorpion toxin. Primary cultures of rat skeletal muscle cells were also negative. Thus specific binding in the nanomolar range seems to be selectively associated with the neuronal phenotype. alpha-Scorpion toxin binding was tested before and after induction of neurites: in N18, NIE-115, NS20 cell lines, the differentiation brought on an increase in the number of binding sites but had little effect on the dissociation constant; in the hybrids NG108-15 and T28 high affinity saturable binding sites were detectable after but not prior to morphological differentiation.
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PMID:High-affinity binding of alpha-scorpion toxin: a neuronal property. 662 54

We have determined the solution structure of an alpha-toxin, CsE-V, isolated from the venom of the New World scorpion Centruroides sculpturatus Ewing (CsE). This toxin causes spontaneous rhythmic contractions in muscle. Unlike other New World toxins from CsE, this protein exhibits amino acid insertions and deletions at locations similar to Old World toxins and may thus represent a transition protein between the New World and Old World scorpion alpha-toxins. Sequence-specific assignments were made using 600 MHz 1H two-dimensional NMR data. NOESY, PH-COSY and amide-exchange data were used to deduce constraints for molecular modeling calculations. Distance geometry and dynamical simulated annealing calculations were performed to generate a family of 70 structures free of constraint violations. With respect to this family of structures, the energy-minimized average structure had root-mean-square deviations of 0.74 and 1.32 A for backbone and all atoms, respectively (excluding the C-terminal dipeptide, which is disordered). As with other scorpion toxins, the secondary structure of CsE-V consists of an alpha-helix, a three-strand anti-parallel beta-sheet, four beta-turns, and a hydrophobic patch that includes tyrosine residues in herringbone configuration. Unlike the CsE-v3 and -v1 proteins from C. sculpturatus, all of the proline residues were found to be in the trans configuration. The alpha-helix is slightly longer in CsE-V. The overall structure is more similar to the Old World alpha-toxin AaH-II from Androctonus australis Hector (r.m.s.d 1.59 A for backbone atoms of matching residues) than to the New World alpha-toxin CsE-v3 (r.m.s.d. 1.91 A). These structural data on CsE-V add further to our knowledge of the conformational repertoire exhibited by these sodium channel-binding neurotoxins.
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PMID:Solution structure of an Old World-like neurotoxin from the venom of the New World scorpion Centruroides sculpturatus Ewing. 773 52

At least six topologically separated neurotoxin receptor sites have been identified on sodium channels that reveal strong allosteric interactions among them. We have studied the allosteric modulation induced by veratridine, binding to receptor site 2, and brevetoxin PbTx-1, occupying receptor site 5, on the binding of alpha-scorpion toxins at receptor site 3, on three different neuronal sodium channels: rat brain, locust, and cockroach synaptosomes. We used 125I-AaH II, the most active alpha-scorpion toxin on vertebrates, and 125I-Lqh alpha IT, shown to have high activity on insects, as specific probes for receptor site 3 in rat brain and insect sodium channels. Our results reveal that brevetoxin PbTx-1 generates three types of effects at receptor site 3:1) negative allosteric modulation in rat brain sodium channels, 2) positive modulation in locust sodium channels, and 3) no effect on cockroach sodium channel. However, PbTx-1 activates sodium channels in cockroach axon similarly to its activity in other preparation. Veratridine positively modulates both rat brain and locust sodium channels but had no effect on alpha-toxin binding in cockroach. The dramatic differences in allosteric modulations in each sodium channel subtype suggest structural differences in receptor sites for PbTx-1 and/or at the coupling regions with alpha-scorpion toxin receptor sites in the different sodium channels, which can be detected by combined application of specific channel modifiers and may elucidate the dynamic gating activity and the mechanism of allosteric interactions among various neurotoxin receptors.
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PMID:Alpha-scorpion toxins binding on rat brain and insect sodium channels reveal divergent allosteric modulations by brevetoxin and veratridine. 779 99

Voltage-sensitive sodium channels are responsible for the initiation of action potentials in many excitable cells. Several neurotoxins bind to distinct receptor sites on sodium channels and reveal strong allosteric interactions among them. Scorpion alpha toxins, which inhibit sodium channel inactivation by binding to receptor site 3, have been very important tools to study sodium channel structure and function. Recently, we have shown that brevetoxin induce a strong negative allosteric modulation on scorpion alpha-toxin binding on rat brain sodium channels, in contrast to previously published studies. In this report we have examined the reasons for this discrepancy and found new, unexpected allosteric interactions between the tetrodotoxin and brevetoxin receptor sites, using scorpion alpha-toxin as sensitive probe for subtle conformational changes on sodium channels. Tetrodotoxin reverses the negative modulation induced by brevetoxin on scorpion alpha-toxin binding, revealing new dynamic interactions in sodium channel structure.
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PMID:Tetrodotoxin reverses brevetoxin allosteric inhibition of scorpion alpha-toxin binding on rat brain sodium channels. 870 72


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