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

The voltage-sensitive sodium channel is generally regarded as the primary target site of dichloro-diphenyl-trichloro-ethane (DDT) and pyrethroid insecticides, and has been implicated in the widely reported mechanism of nerve insensitivity to these compounds. This phenomenon is expressed as knockdown resistance (kdr) and has been best characterised in the housefly where several putative alleles, including the more potent super-kdr factor, have been identified. We report the isolation of cDNA clones containing part of a housefly sodium channel gene, designated Msc, which show close homology to the para sodium channel of Drosophila (99% amino acid identity within the region of overlap). Using Southern blots of insect DNA, restriction fragment length polymorphisms (RFLPs) at the Msc locus were identified in susceptible, kdr and super-kdr housefly strains. These RFLPs showed tight linkage to resistance in controlled crosses involving these strains, thus providing clear genetic evidence that kdr, and hence pyrethroid mode of action, is closely associated with the voltage-sensitive sodium channel.
Mol Gen Genet 1993 Jul
PMID:Knockdown resistance (kdr) to DDT and pyrethroid insecticides maps to a sodium channel gene locus in the housefly (Musca domestica). 810 63

Rapid changes in transglutaminase (TG) activity, 45Ca(2+)-influx and [3H]leucine incorporation in superior cervical ganglia (SCG), and nodose ganglia (NG) excised from adult rats were examined following addition of membrane-depolarizing agents veratridine (Ver) or high extracellular [K+]o during aerobic incubation in vitro at 37 degrees C. Addition of KCl (50 mM) stimulated TG activity to a maximal extent (four to six-fold) in SCG and NG after 30 min. Ver (0.2 mM) also increased TG activity in both ganglia after 30 min. Kinetic studies showed that the stimulation of TG activity in both ganglia caused by each depolarization condition was associated with a decrease in Km and an increase in Vmax value. The depolarizing agents Ver and high [K+]o also caused significant increases in 45Ca2+ influx into both ganglia. The Ver-induced increases in TG activity and 45Ca2+ accumulation were antagonized by tetrodotoxin (TTX, 1 microM), a sodium channel blocker. The K(+)-induced increase in TG activity was not blocked by tetraethylammonium (TEA, 20 mM), a potassium channel antagonist, although TEA did block the K(+)-induced increase in 45Ca2+ accumulation. The membrane-perturbing, sialic acid-containing compounds, GM1-ganglioside (GM1, 5 nM) and alpha-sialyl cholesterol (alpha-SC, 20 microM), were moderate inhibitors of the K(+)-induced effects on TG activity and 45Ca2+ accumulation. The sialyl compounds had little effect on Ver-induced accumulation of 45Ca2+ but enhanced the Ver-evoked stimulation in TG activity. These results suggests that the veratridine- and K(+)-induced increases in TG activity occur via modulation of Ca2+ and Na+ channel gating mechanisms that are pharmacologically distinct for each depolarizing agent. The veratridine- and K(+)-induced decrease in [3H]leucine incorporation could be a result of stimulation of TG activity as a consequence of degenerative alterations.
Mol Chem Neuropathol
PMID:Effects of depolarizing agents on transglutaminase activity, Ca2+ influx, and protein synthesis in superior cervical and nodose ganglia excised from rats. 810 33

Voltage-dependent sodium channels control the transient inward current responsible for the action potential in most excitable cells. Members of this multigene family have been cloned, sequenced, and functionally expressed from various tissues and species, and common features of their structure have clearly emerged. Site-directed mutagenesis coupled with in vitro expression has provided additional insight into the relationship between structure and function. Subtle differences between sodium channel isoforms are also important, and aspects of the regulation of sodium channel gene expression and the modulation of channel function are becoming topics of increasing importance. Finally, sodium channel mutations have been directly linked to human disease, yielding insight into both disease pathophysiology and normal channel function. After a brief discussion of previous work, this review will focus on recent advances in each of these areas.
Mol Neurobiol
PMID:Structure, function and expression of voltage-dependent sodium channels. 817 45

The effects of riluzole, a novel neuroprotective drug with anticonvulsant and anti-ischemic properties, were studied on currents carried by cloned rat brain IIA sodium channel alpha subunits expressed in Xenopus oocytes. (i) When the oocytes were held at strongly hyperpolarized potentials to close the sodium channels and riluzole was added to the external solution, the current elicited by test depolarizing pulses was reduced within a few minutes and recovered upon washout of the riluzole. Although the currents were reduced, riluzole did not shift the peak current-voltage relationship. An inhibitory constant of 30 microM was estimated for the low affinity block of closed channels. (ii) Riluzole did not affect the time course of inactivation, and repetitive stimulation at frequencies that did not result in significant accumulation of inactivation did not affect current block. These results suggest that riluzole did not block open channels. (iii) Riluzole increased steady state inactivation by shifting its voltage dependence in the hyperpolarizing direction, by prolonging the recovery from inactivation, and by blocking more effectively at high stimulation frequencies. According to the modulated receptor theory, these results suggest that riluzole binds selectively to inactivated channels, with an inhibitory constant estimated at 0.2 microM. These results show that the riluzole binding site is on the alpha subunit of the sodium channel, and they suggest that stabilization of the inactivated state may underlie the neuroprotective properties of riluzole.
Mol Pharmacol 1994 May
PMID:Block of the rat brain IIA sodium channel alpha subunit by the neuroprotective drug riluzole. 819 96

The type II pyrethroid fenvalerate is known to depolarize nerve membranes by keeping sodium channels in a very stable modified open state. We have performed experiments on crayfish giant axons to determine whether the asymmetric charge movement was affected in parallel with changes in sodium current. When all sodium channels were modified by repetitive stimulation in the presence of fenvalerate, on gating charge movement was reduced by 78%. When on gating currents were fractionated into three exponentially decaying components, it was found that fenvalerate selectively depressed the intermediate and slow components, leaving the fast component unchanged. Off gating currents could be fractionated into two exponentially decaying components. The fast component of off charge movement (tau = 50 microseconds at -160 mV) was abolished by fenvalerate, whereas the slow component was suppressed by 50%. These results are consistent with previous conclusions that a large fraction of the intermediate and slow on and slow off components and essentially all of the fast off components are related to sodium channel gating. We conclude that fenvalerate traps the gating charges of sodium channels in the open state.
Mol Pharmacol 1993 Apr
PMID:Immobilization of sodium channel gating charge in crayfish giant axons by the insecticide fenvalerate. 838 11

We have used site-directed mutagenesis to examine the functional role of each of the eight acidic amino acid residues in the region between proposed transmembrane segments 5 and 6 (S5-S6) of domain II of the rat brain IIA sodium channel alpha subunit. The mutant sodium channels were expressed in Xenopus oocytes and analyzed by two-microelectrode voltage clamping with respect to voltage-dependent activation, inactivation, ion selectivity, and sensitivity to the pore-blocking neurotoxins tetrodotoxin (TTX) and saxitoxin (STX). None of the mutations had significant effects on voltage-dependent gating, ion selectivity, or block by protons or calcium. Three of the mutations had significant effects on the sensitivity of the channel to block by TTX and STX. Neutralization of negative charges at positions 942 and 945 greatly reduced the block by TTX and STX, suggesting that these two residues interact directly with the toxins. Substitution of a nearby negative charge at position 949 resulted in a smaller decrease in TTX and STX block, although analysis of TTX block of this mutant at low ionic strength suggests that the interaction is not simply by an electrostatic through-space mechanism. None of the other five mutations had any effects on block by either TTX or STX. The two acidic residues that had dramatic effects on toxin binding had significantly smaller effects at a depolarized membrane potential. The sodium channel interacts with TTX and STX with higher affinity at depolarized potentials, so these two residues must make a greater contribution to toxin binding in the low affinity state. These results define a small segment of the sodium channel alpha subunit domain II S5-S6 region that interacts with TTX and STX and therefore must lie near the mouth of the channel pore.
Mol Pharmacol 1993 Apr
PMID:Site-directed mutagenesis of the putative pore region of the rat IIA sodium channel. 838 12

In Drosophila, the para gene has been shown to encode a functional voltage-dependent sodium channel. We used a cDNA clone to study the distribution of its transcripts by in situ mRNA hybridization on adult fly sections. These transcripts are found in cortical regions of the central nervous system and in the eyes. On immunoblots, antibodies raised against expression products of part of the gene recognize a polypeptide of M(r) approximately 270,000 in head membranes. Immunolocalization experiments indicate that anti-para antibodies bind to cortical regions of the brain and give heavy signals in the eyes. Immunohistochemistry was also performed on napts and seits1, two mutant Drosophila strains known to be defective in sodium channel activity. Only napts flies displayed a decrease in the expression of the para protein.
Insect Biochem Mol Biol 1993 Apr
PMID:Transcription analysis of the para gene by in situ hybridization and immunological characterization of its expression product in wild-type and mutant strains of Drosophila. 838 73

We have used a reverse hemolytic plaque assay and frequency distribution of immunoplaque areas to analyze the effect of carbachol (CCh, 100 nM), on insulin secretion by single pancreatic beta-cells. The CCh effect was strongly dependent on the extracellular glucose concentration. Compared with the respective controls in each condition, when glucose was omitted from the incubation medium, CCh induced a 85% increase in the insulin secretion index. In 5.6 mM glucose, CCh induced a 100% increase in the insulin secretion index and this effect was characterized by (1) amplification of the response to glucose, and (2) recruitment of previously silent cells to secretory activity. However, at high glucose concentrations (20.6 mM), the insulin secretion index decreased 49%. CCh effects were blocked by atropine (1 microM). CCh effects were not uniform among beta-cells. The functional subpopulation of beta-cells with the highest secretion rate was preferentially affected by the muscarinic agonist. The specific sodium channel blocker tetrodotoxin prevented CCh-stimulated insulin secretion in basal media, suggesting that voltage-dependent sodium channels are involved in CCh stimulation-secretion coupling in single beta-cells.
Mol Cell Endocrinol 1993 May
PMID:Muscarinic modulation of insulin secretion by single pancreatic beta-cells. 839 96

Malignant hyperthermia (MH) is a potentially lethal pharmacogenetic disease with autosomal dominant inheritance triggered by exposure to commonly used inhalational anaesthetics or depolarising muscle relaxants. A MHS locus has been identified on human chromosome 19q12-q13.2 and the gene for the skeletal muscle calcium release channel of sarcoplasmic reticulum (ryanodine receptor) (RYR1) is considered a candidate for the molecular defect. However, MH has been shown to be genetically heterogeneous, and in the ensuing search for other MHS genes, a locus on chromosome 17q has been proposed, and the gene for the adult muscle sodium channel (SCN4A) was suggested as a candidate. We performed linkage studies using polymorphic microsatellite markers for subunits of the skeletal muscle dihydropyridine (DHP) receptor, CACNL1A3 mapped to chromosome 1q, as well as C-ACNLB1 and CACNLG, the latter two localised on chromosome 17q11.2-q24 in proximity to the proposed MHS2 and the SCN4A loci, and we also included markers for the loci D17S250, D17S579, NM23 (NME1), GH1, and SCN4A from that region. Our results exclude the alpha 1, beta 1 and gamma subunit of the DHP receptor as well as the SCN4A locus from that region. Our results exclude the alpha 1, beta 1, and gamma subunit of the DHP receptor as well as the SCN4A locus as candidates for the molecular defect in MHS for these pedigrees where also the RYR1 on chromosome 19q13.1 has been excluded. A multipoint analysis excludes the disease from the entire 84 cM interval containing the proposed MHS locus on chromosome 17q.(ABSTRACT TRUNCATED AT 250 WORDS)
Hum Mol Genet 1993 Jul
PMID:Exclusion of malignant hyperthermia susceptibility (MHS) from a putative MHS2 locus on chromosome 17q and of the alpha 1, beta 1, and gamma subunits of the dihydropyridine receptor calcium channel as candidates for the molecular defect. 839 39

Pyrethroids, with their lack of persistence and low mammalian toxicity, have been important insecticides since the early 1970s. However, heavy use has selected for resistance to pyrethroids in populations of many insects, in particular the tobacco budworm Heliothis virescens, a major cotton pest in the Americas. Several studies have identified the voltage-gated sodium channel as the principal target of pyrethroid action, and the sodium channel has been implicated in pyrethroid resistance in Musca domestica and Drosophila melanogaster. We present molecular genetic evidence that pyrethroid resistance is linked to a sodium channel locus in a strain of H. virescens. This is the first such evidence for any major agricultural pest, and is an important step towards understanding the molecular basis of resistance. This in turn will facilitate assessment, modeling, and control of resistance in pest populations, and increase our understanding of sodium channel function.
Insect Biochem Mol Biol 1993 Oct
PMID:Linkage of pyrethroid insecticide resistance to a sodium channel locus in the tobacco budworm. 839 35


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