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)

Loop diuretics are widely used drugs; serving to alleviate congestive heart failure and hypertension. Their mechanism of action is considered to be an inhibition of sodium retention in the kidneys, by a block of the Na/K/Cl cotransporter. The ensuing natriuresis and diuresis reduces blood pressure and alleviates congestive heart failure. Several earlier reports suggested direct cardiovascular effects, partly preceding the onset of diuresis. In the present study, evidence is presented for a direct action of two loop diuretic agents, bumetanide and furosemide, on cardiac L-type calcium currents in rabbit ventricular and atrial myocytes. This current is reversibly reduced by micromolar concentrations of these drugs. The onset of this effect can be observed within 1-2s, which could indicate a direct action on the calcium channel, independent of secondary effects subsequent to inhibition of the cotransporter. Thus, part of the therapeutic effects of the loop diuretics may be achieved through a direct reduction of cardiac output.
J Mol Cell Cardiol 1991 Nov
PMID:Loop diuretics block calcium currents in cardiac cells. 180 16

Annexins are a family of water-soluble proteins that bind to membranes in a calcium-dependent manner. Some members have been shown to exhibit voltage-dependent calcium channel activity, a property characteristic of integral membrane proteins. The structures of human annexin V in crystals obtained from aqueous solution and in two-dimensional crystals when bound to phospholipid layers have been determined by X-ray and electron crystallography, respectively. They are compared here. Both structures show close correspondence, suggesting that annexins attach to phospholipid membranes without substantial structural change. These observations, together with biochemical data, lead to the conclusion that annexin V interacts with phospholipid membranes with its convex face. We propose that binding is mediated by direct interaction between the phosphoryl headgroups and the calcium bound to polypeptide loops protruding from the convex face. The membrane area covered by annexin may thus become disordered and permeable allowing calcium flux through the membrane and the central channel-like structure found in annexin molecules.
J Mol Biol 1991 Jul 20
PMID:Structure of soluble and membrane-bound human annexin V. 183 Mar 42

Equilibrium binding studies with the sigma receptor ligand [3H]1,3-di(2-tolyl)guanidine ([3H]DTG) demonstrated two high affinity binding sites in membranes prepared from guinea pig brain. The apparent Kd values of DTG for sites 1 and 2 were 11.9 and 37.6 nM, respectively. The corresponding Bmax values were 1045 and 1423 fmol/mg of protein. Site 1 had high affinity for (+)-pentazocine, haloperidol, (R)-(+)-PPP, carbepentane, and other sigma ligands, suggesting a similarity with the dextromethorphan/sigma 1 binding site described by Musacchio et al. [Life Sci. 45:1721-1732 (1989)]. Site 2 had high affinity for DTG and haloperidol (Ki = 36.1 nM) and low affinity for most other sigma ligands. Kinetic experiments demonstrated that [3H]DTG dissociated in a biphasic manner from both site 1 and site 2. DTG and haloperidol increased the dissociation rate of [3H]DTG from site 1 and site 2, demonstrating the presence of pseudoallosteric interactions. Inorganic calcium channel blockers such as Cd2+ selectively increased the dissociation rate of [3H]DTG from site 2, suggesting an association of this binding site with calcium channels.
Mol Pharmacol 1991 Feb
PMID:Labeling by [3H]1,3-di(2-tolyl)guanidine of two high affinity binding sites in guinea pig brain: evidence for allosteric regulation by calcium channel antagonists and pseudoallosteric modulation by sigma ligands. 184 95

The expression of proenkephalin A (ProEnk A) mRNA and phenylethanolamine N-methyltransferase (PNMT) mRNA in response to nicotine and to a number of secretagogues was examined in cultured bovine adrenal chromaffin cells. Prolonged incubation with nicotine (10 microM) resulted in a 2-fold increase in ProEnk A mRNA but had no significant effect on the level of PNMT mRNA. Similarly, prolonged stimulation with high K+ (56 mM) induced a time-dependent elevation in the level of ProEnk A mRNA reaching 4-fold basal level after 24 h incubation. By contrast, the level of PNMT mRNA was not changed by treatment with high K+. The increase in the level of ProEnk A mRNA by high K+ was abolished by the presence of 10 microM D600, a calcium channel blocker. Unlike the effects of high K+, treatment of the cells with the sodium channel activator veratridine significantly elevated the levels of both ProEnk A and PNMT mRNA. This increase in ProEnk A and PNMT mRNA levels was however less affected by D600. Stimulation of the cells with Ba2+ (1.1 mM) also stimulated the levels of ProEnk A and PNMT mRNA and this action required the presence of extracellular Ca2+. This was in contrast to the effect of Ba2+ in stimulating catecholamine secretion, which was inhibited by Ca2+ and enhanced in Ca2(+)-free buffer. The results of the present study indicate that membrane depolarization and entry of extracellular Ca2+ play an important role on the regulation of ProEnk A and PNMT mRNAs, in addition to their well-known actions on hormone secretion. Furthermore, these results suggest that the expression of ProEnk A mRNA and PNMT mRNA are under independent regulation in response to secretory stimulation.
Brain Res Mol Brain Res 1991 Jan
PMID:Coordinate and differential regulation of proenkephalin A and PNMT mRNA expression in cultured bovine adrenal chromaffin cells: responses to secretory stimuli. 185 66

We have employed an acute explant system of the rat hypothalamus in vitro, as previously described, to examine the role of calcium and calmodulin in the release of corticotrophin-releasing hormone-41 (CRH-41). Release of CRH-41, as determined by radioimmunoassay, was stimulated in a dose-dependent manner by the membrane-depolarizing agents KCl and veratridine. Stimulation was also observed with the calcium ionophore A23187. The calcium channel blocker verapamil (1-100 mumol/l) inhibited both KCl- and veratridine-induced release in a dose-dependent manner (maximum inhibition of 75% and 60% respectively), thus providing further evidence that calcium entry is required for secretion of CRH-41 following membrane depolarization. Trifluoperazine (1-100 mumol/l), an inhibitor of calmodulin-calcium interaction, decreased both KCl- and veratridine-evoked CRH-41 secretion in a dose-dependent fashion (maximum inhibition of 50% and 30% respectively). Similarly, phenytoin, a calmodulin-dependent kinase inhibitor, in the concentration range of 1-100 mumol/l, also decreased depolarization-induced CRH-41 release in a dose-dependent manner. The basal release of CRH-41 was unaffected by either treatment. Finally, both calmodulin inhibitors (10 mumol/l) decreased CRH-41 release induced by the calcium ionophore A23187 (10 mumol/l). These data provide evidence for the role of calcium in membrane depolarization-induced stimulus-secretion coupling of rat hypothalamic CRH-41. Furthermore, inhibition of the stimulatory responses by two separate classes of calmodulin inhibitors suggests a role for calmodulin, at least in part, in this process.
J Mol Endocrinol 1991 Aug
PMID:Involvement of calmodulin in depolarization-induced release of corticotrophin-releasing hormone-41 from the rat hypothalamus in vitro. 189 43

The effects of the calcium/calmodulin signaling system on expression of the rat PRL gene were studied in rat pituitary GH3 cells using two specific naphthalene sulfonamide calmodulin (CaM) antagonist drugs, W7 and a more potent and more highly specific iodo-derivative, 5-iodo-1-C8. PRL (but not GH) mRNA accumulation was markedly inhibited by W7, which in coincubations abolished the stimulation normally seen with TRH. Transient transfection assays showed that expression of the reporter gene chloramphenicol acetyl transferase (CAT) linked to 5'-flanking sequences from the PRL gene was inhibited by the calcium-channel blocker verapamil and by the two CaM antagonists. The calcium effects showed partial promoter specificity, in that transcription of PRL-CAT constructs was markedly inhibited by verapamil, but the Rous sarcoma virus-CAT construct also showed significant inhibition, whereas the pBL-CAT2 construct was unaffected. Three hundred ninety five base pairs were sufficient to confer the full inhibitory effect of calcium channel blockade or CaM antagonist seen with longer constructs. The data indicate that CaM is important for PRL gene transcription, and that the effects of CaM are exerted on DNA sequences within the proximal 395bp of prolactin 5'-flanking DNA.
Mol Endocrinol 1991 Jan
PMID:Calcium/calmodulin regulation of the rat prolactin gene is conferred by the proximal enhancer region. 190 54

Leishmania donovani, the etiological agent for the disease visceral leishmaniasis, attach themselves to the macrophages for initiation of the disease. The attachment process has been found to be regulated by Ca2+ ions. Verapamil, a Ca(2+)-channel blocker inhibits Leishmania-macrophage attachment. The inhibitory effect is increased with time. Nifedipine, another Ca(2+)-channel blocker exhibits the same effect. The attachment process is stimulated by Ca(2+)-ionophore alone. The inhibitory effects of the calcium channel blockers are reversed by the ionophore.
Mol Cell Biochem 1991 Mar 27
PMID:Role of Ca2+ ion on Leishmania-macrophage attachment. 190 82

Basal and receptor-regulated changes in cytoplasmic calcium concentration ([Ca2+]i) were monitored by fluorescence analysis in individual rat pituitary gonadotrophs loaded with the calcium-sensitive dye indo-1. Most gonadotrophs exhibited low amplitude spontaneous oscillations in basal [Ca2+]i that were interspersed by quiescent periods and abolished by removal of extracellular Ca2+ or addition of calcium channel blockers. Such random fluctuations in [Ca2+]i, which reflect the operation of a plasma membrane oscillator, were not coupled to basal gonadotropin secretion. The physiological agonist GnRH induced high amplitude [Ca2+]i oscillations; when a threshold [Ca2+]i level was reached, a cytoplasmic oscillator began to generate extremely regular Ca2+ transients. The time required to reach the threshold [Ca2+]i level was inversely correlated with agonist dose; the frequency, but not the amplitude, of agonist-induced Ca2+ spiking increased with agonist concentration. The duration of the latent period decreased and the frequency of Ca2+ spiking increased with the increase in ambient temperature. At high GnRH concentrations, the calcium transients merged into biphasic responses similar to those observed in cell suspensions at all GnRH concentrations. The presence of spontaneous fluctuations in basal [Ca2+]i did not significantly change the patterns of agonist-induced [Ca2+]i responses. Also, removal of extracellular Ca2+ did not interfere with the frequency or amplitude of Ca2+ spikes, but caused the loss of the plateau phase. Blockade of intracellular Ca(2+)-ATPase pumps by thapsigargin was usually accompanied by a subthreshold increase in [Ca2+]i. In such cells the agonist-induced oscillatory pattern was transformed into the biphasic response. In about 10% of the cells, however, high thapsigargin concentrations induced coarse [Ca2+]i oscillations; subsequent stimulation of such cells with GnRH was ineffective. The cytoplasmic oscillatory and biphasic responses may represent a mechanism for differential activation of Ca(2+)-dependent enzymes and their dependent cellular processes, including hormone secretion. The membrane oscillator is probably responsible for refilling of agonist-sensitive pools during and after agonist stimulation.
Mol Endocrinol 1991 Jul
PMID:Spontaneous and agonist-induced calcium oscillations in pituitary gonadotrophs. 194

We have cloned DNA sequences extending up to 6000 bp upstream from the first exon of the human prolactin (hPRL) gene. 5000 bp of these upstream sequences were fused to a CAT reporter gene and shown to provide tissue-specific transient expression in rat pituitary GH3 cells. Multihormonal response was found in this transient expression assay, leading to significant 2- to 5-fold induction by addition of 8-chlorophenylthio-cyclic AMP, thyrotropin-releasing hormone, epidermal growth factor, basic fibroblast growth factor, phorbol myristate acetate, a calcium channel agonist (Bay K-8644) and triiodothyronine. A 3-fold inhibition was observed in the presence of the glucocorticoid agonist dexamethasone. The sequence of the hPRL promoter was determined up to coordinate -3470. Computer similarity search between the rat and human sequences showed two highly conserved regions corresponding to the proximal and distal tissue specific enhancers described in both PRL promoters.
Mol Cell Endocrinol 1991 Sep
PMID:Multihormonal regulation of the human prolactin gene expression from 5000 bp of its upstream sequence. 195 81

Tyrosine hydroxylase is activated and phosphorylated following treatment of PC-12 cells with bradykinin. In order to determine the mechanisms by which this occurs, we have evaluated the second messenger systems that may be responsible for this activation and phosphorylation. Inositol phosphates appear to play an important role in the activation and phosphorylation of tyrosine hydroxylase because bradykinin treatment significantly increased the formation of [3H]inositol phosphates and the concentration of intracellular free calcium ([Ca2+]i) in PC-12 cells. The uptake of extracellular 45Ca2+ into PC-12 cells at 1 min was significantly increased (107%) by bradykinin treatment and this increase was blocked by La3+, an inorganic calcium channel inhibitor, but not by nifedipine, an inhibitor of voltage-dependent calcium channels. The activation of tyrosine hydroxylase in PC-12 cells following bradykinin treatment was partially inhibited by La3+. Additivity experiments were performed to evaluate whether the activation and phosphorylation of tyrosine hydroxylase in PC-12 cells following treatment with bradykinin (10 microM) was similar to the activation and phosphorylation of tyrosine hydroxylase in PC-12 cells following treatment with dibutyryl cAMP (2 mM), 4 beta-phorbol-12 beta-myristate-13 alpha-acetate (PMA) (2 microM), and high K+ (56 mM). The combination of bradykinin and PMA produced additive effects, indicating that the activation of tyrosine hydroxylase by treatment with these two compounds was through different mechanisms. Furthermore, exposure of PC-12 cells to bradykinin did not increase intracellular cAMP levels. The combination of bradykinin and PMA treatments produced only partial additivity in tyrosine hydroxylase activity and phosphorylation. No additivity was produced with bradykinin and high K-treatment. Phosphopeptide analysis was performed on tyrosine hydroxylase obtained from PC-12 cells treated with bradykinin. Bradykinin treatment produced a significant incorporation of [32P]-phosphate into two phosphopeptides of tryptically digested tyrosine hydroxylase. One of these peptides corresponds to a peptide obtained by trypsinization of purified tyrosine hydroxylase that is phosphorylated by purified calcium/calmodulin-dependent protein kinase. The other 32P-tyrosine hydroxylase-peptide obtained from PC-12 cells treated with bradykinin corresponds to the phosphorylation site obtained during PMA stimulation of PC-12 cells. These results indicate that bradykinin treatment increases intracellular inositol phosphates, calcium, and possibly diacylglycerol levels in PC-12 cells. These effects could then increase calcium/calmodulin-dependent protein kinase activity and possibly calcium/phospholipid-dependent protein (protein kinase C) activity, resulting in increased phosphorylation and activity of tyrosine hydroxylase.
Mol Pharmacol 1990 Jan
PMID:Regulation of tyrosine hydroxylase activity in pheochromocytoma PC-12 cells by bradykinin. 196 17


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