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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A myriad of gene induction events underlie nerve growth factor (NGF)-induced differentiation of PC12 cells. To dissect the signal transduction pathways which lead to NGF actions, we have assessed the relative roles of NGF receptor, Src, Ras, and Raf activities in mediating specific gene inductions. We have used the PC12 cell line as well as sublines which inducibly express activated forms of either Src, Ras, or Raf or a dominant inhibitory form of Ras (p21N17 Ras) to study the expression of multiple NGF-inducible mRNAs. The NGF induction of NGFI-A, transin, and VGF mRNAs was mimicked by activated forms of Src, Ras, or Raf and was blocked by p21N17 Ras. The NGF induction of SCG10 mRNA was mimicked only by activated Src and Ras and was blocked by p21N17 Ras, while the induction of Thy-1 mRNA was mimicked only by activated Src and was not blocked by p21N17 Ras. The NGF induction of mRNAs for two sodium channel types was neither mimicked by any activated oncoprotein nor blocked by p21N17 Ras. From these and previous results, we suggest a model in which a linear order of NGF receptor, Src, Ras, and Raf activities is used by NGF to elicit gene inductions. These signaling components define branchpoints in the pathway to specific gene induction events, providing a mechanism for generating a host of diverse NGF actions.
Mol Cell Biol 1993 Jun
PMID:A branched signaling pathway for nerve growth factor is revealed by Src-, Ras-, and Raf-mediated gene inductions. 849 45

Long QT syndrome (LQT) is an inherited cardiac disorder that causes syncope, seizures and sudden death from ventricular tachyarrhythmias. We used single-strand conformation polymorphism (SSCP) and DNA sequence analyses to identify mutations in the cardiac sodium channel gene, SCN5A, in affected members of four LQT families. These mutations include two identical intragenic deletions and two missense mutations. These data suggest that SCN5A mutations cause LQT. The location and character of these mutations suggest that this form of LQT results from a delay in cardiac sodium channel fast inactivation or altered voltage-dependence of inactivation.
Hum Mol Genet 1995 Sep
PMID:Cardiac sodium channel mutations in patients with long QT syndrome, an inherited cardiac arrhythmia. 854 46

Corticosteroid regulation of Na/K-ATPase is of key importance in the modulation of Na+ transport across renal tubular epithelia. In amphibian renal cells, aldosterone induction of Na/K-ATPase alpha 1 and beta 1 subunit gene transcription is mediated by an indirect mechanism dependent on the synthesis of a labile protein. In mammalian target cells, while both mineralo- and glucocorticoids increase the levels of Na/K-ATPase alpha 1 and beta 1 subunit mRNA and enzyme activity, they are diminished by glycyrrhetinic acid (GE), the active ingredient of licorice. To investigate the mechanisms underlying the regulation of mammalian renal Na/K-ATPase, levels of alpha 1 and beta 1 mRNA were measured in rat kidney epithelial (NRK-52E) cells treated with a range of concentrations of aldosterone, corticosterone and GE in the presence of a specific inhibitor of mRNA synthesis, dichlororibofuranosylbenzimidazole (DRB), an inhibitor of total RNA synthesis, actinomycin D (ActD), and the protein synthesis inhibitor cycloheximide (CHX). In addition, GE was co-incubated with the sodium channel antagonist benzamiloride (BZ). The increase in both alpha 1 and beta 1 mRNA levels following aldosterone and corticosterone was completely abolished by treatment with ActD and DRB, while CHX did not affect this response. Similarly, the GE-induced decrease in alpha 1 and beta 1 mRNA was also completely abolished by ActD and DRB, but not by CHX or by BZ. The half-lives of alpha 1 and beta 1 mRNA in these cells (means +/- S.E.M., n = 4), estimated from the rate of mRNA decay in the presence of DRB, were 6.8 +/- 0.3 and 4.8 +/- 0.2 h respectively. This was unaffected by GE. The inhibitory action of GE on alpha 1 and beta 1 mRNA levels was accompanied by a dose-dependent decrease in levels of intracellular cAMP (means +/- S.E.M., n = 4) from 395 +/- 28 fmol cAMP/microgram total cell protein to between 275 +/- 19 fmol/micrograms total cell protein (0.1 microM GE) and 78 +/- 11 fmol/micrograms total cell protein (10 microM GE). This was abolished following down-regulation of protein kinase C by prolonged treatment with the phorbol ester tetradecanoylphorbol-13-acetate (TPA), and by pertussis toxin (PT), but not by cholera toxin (CT). Indeed, subunit mRNA levels were increased by 8-bromo-cAMP (2.2-fold) and stimulators of adenylate cyclase activity, i.e. forskolin (2.1-fold), PT (2.1-fold) and CT (1.9-fold), but not by TPA.(ABSTRACT TRUNCATED AT 400 WORDS)
J Mol Endocrinol 1995 Aug
PMID:Transcriptional regulation of Na/K-ATPase by corticosteroids, glycyrrhetinic acid and second messenger pathways in rat kidney epithelial cells. 854 17

Coexpression of the rat beta 1 subunit with rat brain and skeletal muscle sodium channel alpha subunits in Xenopus oocytes normalizes currents by accelerating sodium current decay kinetics, shifting steady state availability relationships, and accelerating recovery from inactivation. Unlike brain and skeletal muscle, the heart alpha subunit expressed without beta 1 has native-like decay kinetics in oocytes. Messenger RNA for beta 1 has been found in heart, but whether and how it affects cardiac sodium channel function are unclear. We studied coexpression of human heart alpha subunit with beta 1 in Xenopus oocytes using two microelectrode voltage-clamp and macropatch techniques. Coexpression with beta 1 caused a significant positive shift of 3-7 mV in the midpoint of the steady state inactivation relationship but did not affect single-channel conductance, activation, current decay, or recovery from inactivation. Sensitivity to lidocaine block, however, was decreased for both resting state block (Kd = 0.5-1.3 mM) and phasic block in response to pulse trains, but inactivated state block was not affected (Kd = approximately 10 microM). Coexpression with beta 1 increased the rate of recovery from lidocaine block, which accounted for the major part of the observed differences in tonic and phasic block. A beta 1 construct with the cytoplasmic tail removed also produced these effects, demonstrating that the beta 1 cytoplasmic tail was not involved in altering lidocaine block. We conclude that the beta 1 subunit is capable of affecting function of the cardiac sodium channel in oocytes by decreasing tonic and phasic lidocaine block with small effects on gating.
Mol Pharmacol 1996 Jan
PMID:Coexpression of beta 1 with cardiac sodium channel alpha subunits in oocytes decreases lidocaine block. 856 9

The sodium channel blocker propafenone and a series of analogs have been identified as effective modulators of P-glyco-protein-mediated multidrug resistance in human tumor cells. A series of closely related structural homologues showed a highly significant correlation between lipophilicity and pharmacological effect. Reduction of the carbonyl group as well as conversion to a methylether led to a remarkable decrease in activity, whereby lipophilicity lost its predictive character as the main determinant for modulator potency. Similarly, the relative positioning of the acyl- and propanolamine side chains also influences activity, so the distance between carbonyl group and nitrogen atom seems important.
Mol Pharmacol 1996 Jun
PMID:Structural requirements for activity of propafenone-type modulators in P-glycoprotein-mediated multidrug resistance. 864 52

Normal, and perhaps pathological, characteristics of neuronal excitability are related to the distribution and density of voltage-gated ion channels such as the sodium channel. We studied normal and epileptic human brain using the ligase detection reaction to measure the relative quantities of mRNAs encoding sodium channel subtypes 1 and 2. Normal brains exhibited characteristic 1:2 ratios which varied by brain region, but the ratios were invariate among individuals. These normal values were altered as much as threefold in anatomically corresponding regions of epileptic brain tissues. Changes of this magnitude in such a highly conserved value support a potential role for sodium channels in the pathophysiology of epilepsy.
Brain Res Mol Brain Res 1996 Jan
PMID:Altered brain sodium channel transcript levels in human epilepsy. 871 43

The expression of rat brain sodium channel alpha-subunit (Na+I, Na+II and Na+III) and beta 1-subunit mRNAs was examined in rat fetal brain neurons in culture. A combined technique of reverse transcription and polymerase chain reaction (RT-PCR) was used. Two different PCR primer sets were designed to obtain simultaneous amplification of the three alpha-subunit mRNAs. All three molecules were detected in fetal neurons but the expression pattern (Na+III > Na+II > > Na+I) was different than that observed in adult tissue (Na+II > Na+I > Na+III). Expression of the beta 1-subunit mRNA was detected using a specific PCR primer set. Doublet bands were amplified, from fetal cells and adult brain mRNA. To get further insight into the molecular mechanism that underlie activity dependent plasticity of sodium channels, we studied the effect on the expression of sodium channel subunits mRNA of a 60 h incubation of cells in the presence of a scorpion neurotoxin that blocks channel inactivation. An overall decrease in the expression of all three alpha-subunit mRNAs was observed whereas the beta 1-subunit mRNA was unaffected by the same treatment. When cells were incubated with the scorpion neurotoxin together with tetrodotoxin, to block Na+ influx through channels, the decrease in mRNA expression was not observed. Finally, a 60 h continuous depolarization of cells induced by application of a high concentration KC1 solution did not mimic the effect of the scorpion toxin. These observations suggest that a persistent activation of the sodium channels is able to down-regulate mRNA expression for alpha-subunits but not for the beta 1-subunit.
Brain Res Mol Brain Res 1996 Apr
PMID:Channel activators reduce the expression of sodium channel alpha-subunit mRNA in developing neurons. 873 42

The sodium channel beta 1 subunit (Na beta 1) is a component of the rat brain voltage-dependent sodium channel. We have used nonradioactive in situ hybridization cytochemical techniques to demonstrate that transcript levels of Na beta 1 are differentially upregulated during postnatal development of several CNS regions, with selective labeling of specific neuronal populations. In the hippocampus, labeling of the pyramidal cell layer (particularly in the CA3 region) and dentate granule cells was initially observed at postnatal day 2 (P2) and P10, respectively, and became progressively more intense with maturation. Labeled cells were first observed in the hilus at P10. In the developing cerebellum, transient labeling was observed in the external granule cell layer beginning at P1 while label increased in the internal granule cell layer up to P21. Purkinje cells showed significant label beginning at P4 and increasing up to P21. Weak signal was seen in neurons of deep nuclei at P1 and increased up to P21. Na beta 1 labeling in the spinal cord was first observed in the ventral horn at P2, and the intensity of labeling in these large motoneurons gradually increased. In addition, there was a ventral-dorsal gradient in this region, with label appearing subsequently in neurons of Rexed laminae IX, VII and VIII, and in the dorsal horn (Rexed laminae I-VI). In these regions, the labeling reached a plateau within the first 2-3 weeks after birth and persisted into the adult rat. The time course and regional heterogeneity of Na beta 1 expression are consistent with the hypothesis that the expression of mature Na+ channels, including Na beta 1, contributes to the development of circuitry that supports complex patterns of electrogenesis.
Brain Res Mol Brain Res 1995 Dec 28
PMID:Na+ channel beta 1 subunit mRNA expression in developing rat central nervous system. 875 Aug 27

Transient transfection experiments indicate that a 5'-flanking upstream domain, residing between -437 and -262 bp of the human dopamine beta-hydroxylase (DBH) gene, has a cell type-specific silencer function. This domain contains a putative silencer motif (which we designate DBH negative regulatory element, DNRE), showing sequence homology with the neural-restrictive silencer element (NRSE or RE-1) recently characterized in type II sodium channel, SCG10 and synapsin I genes. When the DNRE was placed at the proximal 262 bp of the homologous (DBH) promoter, it exhibited strong silencer activity both in DBH-expressing SK-N-BE(2)C as well as in DBH-nonexpressing HeLa cells. In addition, the DNRE also exhibited modest silencer activity upon a heterologous tk (herpes simplex virus thymidine kinase) promoter in both cell lines. Electrophoretic mobility shift assay demonstrated that nuclear extracts from both SK-N-BE(2)C and HeLa cells contain protein(s) that specifically bind to the DNRE. Formation of this DNRE/protein complex was specifically inhibited by an excess of unlabeled DNRE or NRSE. Finally, a similar sequence motif residing in the corresponding upstream area of the rat DBH gene also had a negative regulatory function, indicating that the silencer function of the DNRE is conserved in human and rat DBH genes.
Brain Res Mol Brain Res 1995 Dec 28
PMID:Identification of a negative regulatory element in the 5'-flanking region of the human dopamine beta-hydroxylase gene. 875 Aug 28

Although voltage-sensitive sodium channels play a central role in electrogenesis in neurons, rat brain sodium channels are also present in some glial cells. To determine whether rat brain sodium channel alpha-subunit isotypes are expressed in other cell types, we examined osteoblasts within the embryonic day 17 (E17) vertebral column with in situ hybridization and immunocytochemical methods. For in situ hybridization studies, riboprobes hybridizing to isoform-specific sequences in the 3'-noncoding region of sodium channel mRNAs (NCI, NCII and NCIII) were utilized. Sodium channel mRNA I and III were not detectable in osteoblasts of the vertebra centrum or neural arches in E17 rats. In contrast, sodium channel mRNA II was moderately expressed by osteoblasts in the developing vertebral column of E17 rats. In immunocytochemical experiments, antipeptide antibodies directed against conserved and isotype-specific regions of the sodium channel alpha-subunit were used. Antibody SP20, which recognizes a conserved region of the sodium channel, intensely stains osteoblasts in both the vertebra centrum and neural arches. Antibody SP11-I, which recognizes sodium channel I, exhibited negligible-to-low levels of immunostaining in vertebral column osteoblasts. Osteoblasts reacted with antibody SP11-II, which recognizes sodium channel II, displayed moderate levels of immunostaining. Antibody SP32-III, which recognizes sodium channel III, displayed negligible levels of staining in osteoblasts within vertebra centrum and neural arches. These results demonstrate that osteoblasts in situ within E17 vertebral columns express sodium channel II mRNA and protein. Together with previous electrophysiological observations, the present results suggest that functional sodium channels are expressed in osteoblasts in vivo. These results extend the range of non-neuronal cells known to express rat brain sodium channels.
Brain Res Mol Brain Res 1995 Dec 01
PMID:Type II brain sodium channel expression in non-neuronal cells: embryonic rat osteoblasts. 875 Aug 64


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