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Query: UNIPROT:P06889 (Mol)
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Hexamethylene bisacetamide (HMBA) is a potent inducer of differentiation of murine erythroleukemia cells (MELC). Commitment, the irreversible initiation of the program of terminal-cell differentiation, is first detected in HMBA-sensitive DS19-SC9 MELC in culture after 10 to 12 h of exposure to HMBA. Vincristine (VC)-resistant MELC derived from the DS19-SC9 MELC line display increased sensitivity to HMBA and become committed with little or no latent period. In the present study, we showed that the MELC line R1, which is resistant to HMBA-mediated differentiation, became sensitive to inducer if selected for a low level of VC resistance (less than 10 ng of VC per ml). Four independently derived VC-resistant cell lines from HMBA-resistant R1 cells, designated R1[VCR]a to R1[VCR]d, acquired sensitivity to HMBA and the accelerated kinetics of commitment that are characteristic of VC-resistant MELC derived from the parental DS19-SC9 cells. The calcium channel blocker verapamil suppresses the VC resistance of R1[VCR] cells but does not alter the accelerated response to HMBA. In R1[VCR] cells there was no detectable increase in the level of the 140-kilodalton P-glycoprotein. Transient inhibition of protein synthesis during the latent period delays inducer-mediated commitment of VC-sensitive DS19-SC9 MELC but does not alter the accelerated commitment kinetics of R1[VCR]a cells. Previously, we have reported evidence that protein kinase C beta (PKC beta) plays a role in HMBA-induced MELC differentiation and that compared with DS19-SC9 cells, R1 cells have a relatively low level and R1[VCR]a cells have a high level of PKC beta. These findings suggest that (i) acquisition of VC resistance overcomes the block acquired by R1 cells to HMBA-mediated differentiation; (ii) the accelerated kinetics of HMBA-induced commitment of VC-resistant MELC is not dependent on the verapamil-sensitive transport channel that is responsible, at least in part, for resistance to VC; (iii) in VC-resistant MELC, there is constitutive expression or accumulation of a protein required for HMBA-induced differentiation; and (iv) an elevated level of PKC beta activity may play a role in the altered response of R1[VCR] and other VC-resistant MELC to HMBA.
Mol Cell Biol 1990 Jul
PMID:Conversion of differentiation inducer resistance to differentiation inducer sensitivity in erythroleukemia cells. 197 44

Membrane depolarization has been widely used to elucidate the response of the nervous system to prolonged neuronal activity or stress. We studied the effect of treating PC12 cells with membrane depolarizing stimuli, 50 mM KCl, or 150 microM veratridine, and the subsequent changes in the mRNA levels of the catecholamine biosynthetic enzymes, tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH). TH mRNA levels were found to increase 2- to 5-fold after continuous treatment for 1-12 h with 50 mM KCl. Depolarization with 150 microM veratridine had a similar effect on TH mRNA. In contrast, DBH mRNA levels were unchanged by either KCl or veratridine treatment. The role of calcium in the increase of TH mRNA levels elicited by depolarization was examined. The increase in TH mRNA was inhibited by the chelation of calcium with 3 mM EGTA. However, in contrast to their effect on phosphorylation of TH elicited by acute depolarization, the calcium channel blockers, nitrendipine and verapamil, and the calmodulin antagonists, W7 and trifluoperazine, did not prevent the increase in TH mRNA levels subsequent to several hours exposure to depolarizing stimuli. The calcium ionophore, A23187, alone was unable to induce TH mRNA levels. Thus, the increase in TH mRNA elicited by depolarization is mediated differently than the acute phosphorylation of the enzyme.
Brain Res Mol Brain Res 1990 Jul
PMID:Differential effect of membrane depolarization on levels of tyrosine hydroxylase and dopamine beta-hydroxylase mRNAs in PC12 pheochromocytoma cells. 197 98

The involvement of the calcium messenger system in the control of steroidogenesis in the rat and bovine adrenal cortex has been studied extensively. However the role of these second messengers in the control of human adrenocortical function is not established. This was therefore studied by incubating collagenase-dispersed human adrenocortical cells with the calcium ionophore A23187 and the protein kinase C activator phorbol 12-myristate 13-acetate (TPA). The effects of the calcium channel blocker verapamil on basal and stimulated steroidogenesis were also studied. Both TPA (1 pmol/l-10 mumol/l) and A23187 (1 nmol/l-10 mumol/l) caused a dose-dependent increase in cortisol, aldosterone and corticosterone production. Verapamil (10 mumol/l) inhibited the increase in aldosterone, corticosterone and cortisol produced in response to ACTH(1-24), potassium, and desacetyl-alpha MSH. Unlike previous results in the rat, these effects were not specific for aldosterone secretion. The results suggest that, as in other species, calcium mobilization and protein kinase C activation have a role in the control of steroidogenesis in the human adrenal cortex. However, in contrast to the rat, these mechanisms appear to be involved in the control of steroidogenesis in both the zona glomerulosa and inner zone cells.
J Mol Endocrinol 1991 Feb
PMID:Control of steroidogenesis by the calcium messenger system in human adrenocortical cells. 201 56

Mechanisms of atrial natriuretic peptide (ANP) release were studied in neonatal rat heart atrial and ventricular myocytes cultured on Cytodex 3 microcarriers. For simultaneous observations of cytosolic free calcium concentration ([Ca2+]f) and ANP secretion, the culture was packed in a chromatography column, inserted into the cell holder of a spectrofluorometer was perifused with a buffer solution. [Ca2+]f was measured by the fluorescent calcium indicator Fura-2 and ANP in the effluent perfusate by radioimmunoassay. No cell damage was observed and the basal ANP secretion rate and [Ca2+]f were comparable with values obtained by other methods. K(+)-induced depolarization raised [Ca2+]f by 50%, but it rapidly declined again to a steady level 10-20% above the baseline. The calcium channel agonist Bay k8644 elicited a similar temporal pattern of [Ca2+]f changes and 1 microM ionomycin induced a 100-fold increase in [Ca2+]f with a slow re-establishment of the original baseline. None of these stimuli increased the ANP secretion rate of the atrial or ventricular myocytes. Protein kinase C activation by 12-O-tetradecanoyl-phorbol-13-acetate (TPA) stimulated ANP secretion from the atrial myocytes, while the ventricular myocytes were unresponsive to TPA. It is concluded that Ca2+ is not the main mediator in the regulation of ANP release in cultured neonatal heart cells.
Mol Cell Endocrinol 1990 Oct 22
PMID:Cytosolic Ca2+ during atrial natriuretic peptide secretion from cultured neonatal cardiomyocytes. 214 32

The Ca2+ uptake activity of rat cardiac sacroplasmic reticulum (CSR) in ventricular homogenates is highly unstable, and this instability probably accounts for the low specific activity of Ca2+ uptake in previously reported fractions of isolated rat CSR. The instability was observed at either 0 degrees or 37 degrees, but the Ca2+ uptake activity was relatively stable at 25 degrees. The decay of Ca2+ uptake activity at 0 degrees could not be prevented by either PMSF or leupeptin, but dithiothreitol exerted some protective effects. Sodium metabisulfite prevented decay of the Ca2+ uptake activity of homogenates kept on ice but not of homogenates kept at 37 degrees. We also found that release of the CSR from the cellular debris required homogenization in high KCl. This distinguishes rat CSR from canine CSR. Isolated CSR was produced by a combination of differential centrifugation and discontinuous sucrous gradient centrifugation. The average rate of the sustained oxalate-supported calcium uptake in the resulting CSR fraction was 0.36 mumol/min-mg in the absence of CSR calcium channel blockers and 0.67 mumol/min/mg in the presence of 10 microM ruthenium red. Thus, this preparation has the advantage of containing both the releasing and non-releasing fractions of the CSR. The Ca2(+)-ATPase rates averaged 1.07 mumol/min/mg and 0.88 mumol/min-mg in the absence and presence of ruthenium red, respectively. Although these rates are higher than previously reported rates, this CSR preparation should still be considered a 'crude' preparation. A major distinction between the rat CSR and dog CSR was the lower content of Ca2(+)-ATPase in rat CSR, as judged by SDS-PAGE. Preparations of CSR isolated by this method may be useful in evaluating alterations in CSR function.
Mol Cell Biochem 1990 Dec 03
PMID:Stabilization of rat cardiac sacroplasmic reticulum Ca2+ uptake activity and isolation of vesicles with improved calcium uptake activity. 214 64

Maitotoxin (MTX) increases formation of [3H]inositol phosphates from phosphoinositides and release of [3H]arachidonic acid from phospholipids in pheochromocytoma PC12 cells. Formation of [3H]inositol phosphates is detected within 1 min of incubation even with concentrations as low as 0.3 ng/ml (90 pm) MTX, whereas release of [3H]arachidonic acid is not detected until 20 min even with concentrations as high as 1 ng/ml (300 pm) MTX. Stimulation of arachidonic acid release can be detected at 0.03 ng/ml (9 pm) MTX, whereas 0.1 ng/ml (30 pm) MTX is the threshold for detection of phosphoinositide breakdown. Organic and inorganic calcium channel blockers, except Cd2+ and a high concentration of Mn2+, have no effect on MTX-elicited phosphoinositide breakdown, whereas inorganic blockers (e.g., Co2+, Mn2+, Cd2+), but not organic blockers (nifedipine, verapamil, diltiazem), inhibit MTX-stimulated arachidonic acid release. All calcium channel blockers, however, inhibited MTX-elicited influx of 45Ca2+ and the MTX-elicited increase in internal Ca2+ measured with fura-2 was markedly reduced by nifedipine. MTX-elicited phosphoinositide breakdown and arachidonic acid release are abolished or reduced, respectively, in the absence of extracellular calcium plus chelating agent. The calcium ionophore A23187 has little or no effect alone but, in combination with MTX, A23187 inhibits MTX-elicited phosphoinositide breakdown and enhances arachidonic acid release, the latter even in the absence of extracellular calcium. The results suggest that different sites and/or mechanisms are involved in stimulation of calcium influx, breakdown of phosphoinositides, and release of arachidonic acid by MTX.
Mol Pharmacol 1990 Feb
PMID:Maitotoxin: effects on calcium channels, phosphoinositide breakdown, and arachidonate release in pheochromocytoma PC12 cells. 215 71

The diacylglycerol kinase inhibitor monooleoylglycerol (MOG) produced a dose-dependent increase in both phosphoinositide (PI) hydrolysis and insulin secretion in the presence of a substimulatory glucose level (2.75 mM). This effect could not be reproduced by the combination of oleic acid plus glycerol, potential metabolic products derived from MOG catabolism. At a level (25 microM) which has no significant effect on beta cell insulin secretion or PI hydrolysis in the presence of 2.75 mM glucose, MOG significantly potentiated the insulin stimulatory effect of the sulfonylurea tolbutamide (200 microM) in the presence of 7 mM glucose. This heightened insulin secretory response and PI hydrolysis were effectively attenuated by the calcium channel blocker nitrendipine (0.5 microM). These findings indicate that MOG has complex effects on beta cell performance. It promises, however, to be a useful probe in assessing how events associated with increases in PI hydrolysis influence insulin secretion.
Mol Cell Endocrinol 1990 Jan 22
PMID:Influence of monooleoylglycerol on islet cell phosphoinositide hydrolysis and insulin secretion. 215 36

The role of cyclic AMP (cAMP), calcium, calmodulin and protein kinase C (PKC) in the expression of both mouse mammary tumour virus (MMTV) RNA and an MMTV glycoprotein, gp58, was investigated in normal mammary epithelium in culture. None of these second messengers had any effect on MMTV RNA. Dibutyryl cAMP alone had no effect on gp58 levels but, at low concentrations (0.05-0.1 mM), it nearly doubled the induction seen with insulin, cortisol and prolactin; higher concentrations were inhibitory. Although a calcium ionophore (A23187), either alone or with hormones, was ineffective, a calcium channel blocker (verapamil) reduced hormonal induction of gp58 by 80%, and a calmodulin inhibitor (W-13) reduced it by 90%. Two PKC activators, a phorbol ester and a diacylglyceride, were ineffective alone, with hormones or with the calcium ionophore. The following conclusions can be made: (1) cAMP, calcium and calmodulin play an important role in MMTV expression, (2) these second messengers all act post-transcriptionally, since they do not affect MMTV RNA, and (3) PKC does not appear to have a role in MMTV production in normal mammary epithelium.
J Mol Endocrinol 1990 Aug
PMID:Cyclic AMP and calcium in mouse mammary tumour virus expression: effects and post-transcriptional site of action. 216 7

Our analysis of the solid state conformations of nifedipine [dimethyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinecarboxylate ] and its 1,4-dihydropyridine (1,4-DHP) analogues produced a cartoon description of the important interactions between these drugs and their voltage-dependent calcium channel receptor. In the present study a molecular-level detailed model of the 1,4-DHP receptor binding site has been built from the published amino acid sequence of the alpha 1 subunit of the voltage-dependent calcium channel isolated from rabbit skeletal muscle transverse tubule membranes. The voltage-sensing component of the channel described in this work differs from other reported for the homologous sodium channel in that it incorporates a water structure and a staggered, rather than eclipsed, hydrogen bonded S4 helix conformation. The major recognition surfaces of the receptor lie in helical grooves on the S4 or voltage-sensing alpha-helix that is positioned in the center of the bundle of transmembrane helices that define each of the four calcium channel domains. Multiple binding clefts defined by Arg-X-X-Arg-P-X-X-S 'reading frames' exist on the S4 strand. The tissue selectivity of nifedipine and its analogues may arise, in part, from conservative changes in the amino acid residues at the P and S positions of the reading frame that define the ester-binding regions of receptors from different tissues. The crystal structures of two tissue-selective nifedipine analogues, nimodipine [isopropyl (2-methoxyethyl) 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinecarboxylate ] and nitrendipine [ethyl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3, 5-pyridinecarboxylate] are reported. Nimodipine was observed to have an unusual ester side chain conformation that enhances the fit to the proposed ester-sensing region of the receptor.
J Comput Aided Mol Des 1990 Sep
PMID:Receptor model for the molecular basis of tissue selectivity of 1, 4-dihydropyridine calcium channel drugs. 217 83

The characteristics of high affinity dihydropyridine binding sites were compared in normal and cardiomyopathic hamster hearts to probe for possible defects in the calcium channel which could lead to calcium overload and, in turn, to the muscle necrosis characteristic of cardiomyopathy. Kinetic studies of the temperature dependence of [3H]-nitrendipine binding to ventricular homogenates from 60-day-old normal and cardiomyopathic hamsters showed that, in normal hamsters, the rate of dissociation (0.049 +/- 0.006/min at 25 degrees C) was highly temperature-dependent (Q10 = 4.40 +/- 0.69) and that neither the rate nor the temperature dependence was influenced by disease. The rate of association (1.12 +/- 0.11/min/nM at 25 degrees C) was weakly temperature-dependent (Q10 = 1.25 +/- 0.04) and similarly unaffected by disease. The rate of dissociation of [3H]-nitrendipine was increased by verapamil and decreased by diltiazem with little effect on the association rate. Allosteric interactions of diltiazem and verapamil with the dihydropyridine receptor were identical in normal and cardiomyopathic hearts and, together with the normal temperature sensitivity, show that there is no abnormality at the related binding sites for nitrendipine, verapamil and diltiazem in the calcium channel of the cardiomyopathic heart.
J Mol Cell Cardiol 1990 Sep
PMID:[3H]-nitrendipine binding in normal and cardiomyopathic hamster hearts: modulation by temperature, verapamil and diltiazem. 217 94


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