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Query: UNIPROT:P06889 (Mol)
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The progress of repair in Schizosaccharomyces pombe may be followed during post-irradiation incubation by measuring, after various intervals, the ability of UV- or gamma-irradiated cells to avoid enhanced lethality when exposed to the repair inhibitor caffeine (Gentner and Werner, 1975). This technique has now been used to investigate the effect of inhibition of protein synthesis on repair of UV- and gamma-irradiation-induced damage in this organism. When protein synthesis was inhibited with cycloheximide in UV-irradiated wild-type cells, only a small amount of recovery from caffeine inhibition occurred; this indicated that post-irradiation protein synthesis was required for repair, and in particular for the recombinational repair pathway, which is a major mechanism for repair of UV damage in this organism. In gamma-irradiated wild-type cells, inhibition of post-irradiation protein synthesis reduced the rate of recovery from repair inhibition by caffeine, but full recovery from caffeine-sensitive damage did occur at longer incubation times. We attribute the reduction in rate to the effect of protein synthesis inhibition on the recombinational repair pathway, because this pathway is known to be involved in the repair of both gamma-ray and UV damage. The recovery that took place at the slower rate must reflect a caffeine-sensitive pathway which is involved only in repair of gamma-ray damage and which does not require post-irradiation protein synthesis for activity.
Mol Gen Genet 1976 Apr 23
PMID:Effect of protein synthesis inhibition on recovery of UV- and gamma-irridated Schizosaccharomyces pombe from repair inhibition by caffeine. 127 49

In order to study the conductances of the Sarcoplasmic Reticulum (SR) membrane, microsomal fractions from cardiac SR were isolated by differential and sucrose gradient centrifugations and fused into planar lipid bilayers (PLB) made of phospholipids. Using either KCl or K-gluconate solutions, a large conducting K+ selective channel was characterized by its ohmic conductance (152 pS in 150 mM K+), and the presence of short and long lasting subconducting states. Its open probability Po increased with depolarizing voltages, thus supporting the idea that this channel might allow counter-charge movements of monovalent cations during rapid SR Ca2+ release. An heterogeneity in the kinetic behavior of this channel would suggest that the cardiac SR K+ channels might be regulated by cytoplasmic, luminal, or intra SR membrane biochemical mechanisms. Since the behavior was not modified by variations of [Ca2+] nor by the addition of soluble metabolites such as ATP, GTP, cAMP, cGMP, nor by phosphorylation conditions on both sides of the PLB, a specific interaction with a SR membrane component is postulated. Another cation selective channel was studied in asymmetric Ca2+, Ba2+ or Mg(2+)-HEPES buffers. This channel displayed large conductance values for the above divalent cations 90, 100, and 40 pS, respectively. This channel was activated by microM Ca2+ while its Ca2+ sensitivity was potentiated by millimolar ATP. However Mg2+ and calmodulin modulated its gating behavior. Ca2+ releasing drugs such as caffeine and ryanodine increased its Po. All these features are characteristics of the SR Ca2+ release channel. The ryanodine receptor which has been purified and reconstituted into PLB, may form a cation selective pathway.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Cell Biochem 1992 Sep 08
PMID:Reconstitution and regulation of cation-selective channels from cardiac sarcoplasmic reticulum. 128 Dec 62

The effects of intracellular application of two novel Ca2+ releasing agents have been studied in cultured rat dorsal root ganglion (DRG) neurones by monitoring Ca(2+)-dependent currents as a physiological index of raised free cytosolic Ca2+ ([Ca2+]i). A protein based sperm factor (SF) extracted from mammalian sperm, has been found to trigger Ca2+ oscillations and to sensitize unfertilized mammalian eggs to calcium induced calcium release (CICR). In this study intracellular application of SF activated Ca(2+)-dependent currents in approximately two-thirds of DRG neurones. The SF induced activity was abolished by heat treatment, attenuated by increasing the intracellular Ca2+ buffering capacity of the cells and persisted when extracellular Ca2+ was replaced by Ba2+. In addition, activity could be triggered or potentiated by loading the cells with Ca2+ by activating a series of voltage-gated Ca2+ currents. Ca(2+)-activated inward current activity was also generated by intracellular application of cyclic ADP-ribose (cADPR), a metabolite of NAD+, which causes Ca2+ release in sea urchin eggs. This activity could also be enhanced by loading the cells with Ca2+. The cADPR induced activity, but not the SF induced activity, was abolished by depleting the caffeine sensitive Ca2+ store. Ruthenium red markedly attenuated SF induced activity but had little action on cADPR induced activity or caffeine induced activity. Our results indicate that both SF and cADPR release intracellular Ca2+ pools in DRG neurones and that they appear to act on subtly distinct stores or distinct intracellular Ca2+ release mechanisms, possibly by modulating CICR.
Mol Biol Cell 1992 Dec
PMID:Activation of Ca(2+)-dependent currents in cultured rat dorsal root ganglion neurones by a sperm factor and cyclic ADP-ribose. 128 41

The Schizosaccharomyces pombe sts1+ gene, identified by supersensitive mutations to a protein kinase inhibitor, staurosporine, was isolated by complementation by the use of a fission yeast genomic library. Nucleotide sequencing shows that the sts1+ gene encodes a 453 amino acid putative membrane-associated protein that is significantly similar (26% identity) to the chicken lamin B receptor. It is also highly related (53% identity) to a budding yeast ORF, YGL022. These three proteins contain a similar hydrophobicity pattern consisting of eight or nine putative transmembrane domains. By gene disruption we demonstrate that the sts1+ gene is not essential for viability. These disruptants exhibit pleiotropic defects, such as cold-sensitivity for growth and at the permissive temperature, a supersensitivity to divalent cations and several unrelated drugs including staurosporine, caffeine, chloramphenicol, sorbitol, and SDS. Disruption of the sts1+ gene does not lead to a sensitivity to thiabendazole or hydroxyurea.
Mol Biol Cell 1992 Mar
PMID:Fission yeast sts1+ gene encodes a protein similar to the chicken lamin B receptor and is implicated in pleiotropic drug-sensitivity, divalent cation-sensitivity, and osmoregulation. 132 Sep 60

In the treatment of spasticity, the therapeutic cerebrospinal fluid levels of (+/-)-baclofen, a gamma-aminobutyric acid (GABA)B receptor agonist, are below 1 microM. However, the mechanism of the therapeutic action of (+/-)-baclofen remains unknown, because, for the most part, the action of (+/-)-baclofen on GABAB receptors requires micromolar concentrations. Using fura-2 fluorescence microscopy, intracellular ionized calcium was measured in cerebellar granule neurons. Stimulation of a high affinity GABAB receptor potentiated by 2-3-fold the rise in intracellular calcium observed after depolarization of the cell with a Krebs Ringer's buffered solution containing 40 mM K+. Both GABA (100 nM) and (+/-)-baclofen (10-100 nM) stimulated this high affinity receptor. The potentiation of the depolarization-induced rise in intracellular calcium by (+/-)-baclofen (100 nM) was completely blocked by the GABAB receptor antagonist CGP 35348 (200 microM). Also, the intracellular calcium response induced by the activation of high affinity GABAB receptors was prevented by dantrolene (10 microM). The cerebellar granule neurons contained calcium-induced calcium release (CICR) stores. Caffeine (3 mM) and ryanodine (100 microM) potentiated the depolarization-induced rise in intracellular calcium, and this response to both drugs was blocked by dantrolene (10 microM). Because dantrolene does not prevent the rise in intracellular calcium after cell depolarization (this calcium originated from the influx of extracellular calcium), (+/-)-baclofen acting via the high affinity GABAB receptor indirectly activates the CICR stores, allowing the influx of extracellular calcium to trigger the release of calcium from these dantrolene-sensitive CICR stores. Thus, this high affinity GABAB receptor might become activated during persistent depolarization caused by pathological states and could be a mechanism to be studied for the therapeutic action of (+/-)-baclofen in spasticity.
Mol Pharmacol 1992 Sep
PMID:Stimulation of high affinity gamma-aminobutyric acidB receptors potentiates the depolarization-induced increase of intraneuronal ionized calcium content in cerebellar granule neurons. 132 42

The method of rapid superfusion of the single isolated ventricular myocytes of guinea-pig heart was used in order to inhibit the Na-Ca exchange throughout the physiological contraction-relaxation cycle. Superfusion of the cell at selected intervals during the contraction with the Na,Ca-free solution resulted in increase in its amplitude, increase in time to peak shortening and in delay of relaxation, albeit the cells relaxed before reperfusion of normal Tyrode solution. The largest increase in amplitude of contraction (to 134 +/- 16%) was observed when the effective exchange of the cell's environment was attained approximately 50 ms after the pulse stimulating contraction. The effects declined promptly when the delay was increased beyond 100 ms. In the cells treated with 10 mM caffeine superfusion with the Na,Ca-free solution after the delay of 50-100 ms resulted in decrease in extent of shortening. Increase in delay resulted in slight increase in extent of shortening with respect to control and strong inhibition of relaxation. The strongest effects were observed when the delay was approximately 200 ms. Superfusion of the normal cells and of the cells treated with caffeine between contractions resulted in slight potentiation of the next beat. It is concluded that Na-Ca exchange provides an important mechanism of relaxation and outward Ca2+ transport in the physiological contraction of the ventricular cardiomyocyte.
J Mol Cell Cardiol 1992 Sep
PMID:The effects of blocking the Na-Ca exchange at intervals throughout the physiological contraction-relaxation cycle of single cardiac myocyte. 133 77

Using saponin skinned fibers, we investigated whether decreased myofilament calcium responsiveness and contractile activation may in part contribute to heart failure in an animal model of idiopathic spontaneous cardiomyopathy (SCM). We addressed the question as to whether there are adaptive changes at the level of the thin myofilaments in turkey poults with SCM. The calcium concentration ([Ca2+]) required for 50% activation ([Ca2+]50%) was 0.80 +/- 0.12 microM (n = 12) vs. 0.76 +/- 0.08 microM (n = 12) and the Hill coefficient was 1.98 +/- 0.20 (n = 12) vs. 2.14 +/- 0.38 (n = 12) for control and SCM muscles respectively. Maximal Ca(2+)-activated force was not different between control fibers and fibers from failing hearts (3.83 +/- 0.88 g/mm2 vs. 3.65 +/- 0.39 g/mm2). These data indicate there are no differences in calcium-activation between fibers from control and failing myocardium. The effects of caffeine, an agent that increases myofilament Ca2+ sensitivity, were also studied. Addition of 10 mM caffeine resulted in a 0.06 pCa unit leftward shift of the force-pCa relationship in control hearts and 0.14 pCa units in SCM hearts. Caffeine (30 mM) increased force by 26 +/- 2.1% (n = 7) in control fibers and 44.5 +/- 8.7% (n = 8) in myopathic fibers at a pCa of 6.0. The increased responsiveness of muscles from failing hearts to caffeine indicates adaptive changes at the level of the thin myofilaments. Addition of dibutyryl-3',5'-cyclic-Adenosine Monophosphate (D-cAMP) resulted in a 0.21 pCa rightward shift on the calcium axis to higher intracellular calcium concentrations in control myocardium and 0.38 pCa units in SCM failing myocardium. The muscles were also sinusoidally oscillated at frequencies ranging between 0.01 and 100 Hz. In this analysis the frequency at which dynamic stiffness is minimum is taken as a measure of cross-bridge cycling rate. In control muscles, the frequency of minimum stiffness (fmin) was 1.20 +/- 0.11 (n = 4) whereas it was 0.71 +/- 0.08 Hz (n = 4) in myopathic muscles. The addition of 10 microM D-cAMP shifted fmin from 1.20 +/- 0.11 Hz to 1.68 +/- 0.09 Hz (delta = 0.48 +/- 0.06) in control fibers whereas in SCM fibers it caused greater shift of fmin from 0.71 +/- 0.08 Hz to 1.73 +/- 0.08 Hz (delta = 1.02 +/- 0.07). This differential effect of D-cAMP indicates adaptive changes at the level of the myofilaments.(ABSTRACT TRUNCATED AT 400 WORDS)
J Mol Cell Cardiol 1992 Dec
PMID:Calcium-activated force in a turkey model of spontaneous dilated cardiomyopathy: adaptive changes in thin myofilament Ca2+ regulation with resultant implications on contractile performance. 133 13

The effect of altering intracellular free Ca2+ on juvenile hormone (JH) and acid synthesis by larval and pupally-committed corpora allata (CA) of fifth stadium Manduca sexta was investigated. Larval CA required extracellular Ca2+ greater than or equal to 0.1 mM for maximal JH synthesis, while JH acid synthesis by glands after pupal commitment was independent of extracellular Ca2+. Free Ca2+ in the hemolymph ranged from 1.4 to 2.1 mM during the fifth stadium. Both calcium ionophores and caffeine, which releases Ca2+ from intracellular stores, inhibited JH synthesis by larval CA but stimulated JH acid synthesis by post-commitment CA. These results suggest that intracellular stores may be the principal source of Ca2+ for the biosynthetic activity of the post-commitment gland. Calcium channel blockers (La3+, Cd2+) and antagonists (verapamil, isradipine and nitrendipine) decreased both JH and JH acid synthesis, indicating the existence of Ca2+ channels in the CA cell membrane. Calmodulin (CaM) antagonists inhibited the activity of both larval and post-commitment CA, suggesting an integral relationship of CaM to the effects of Ca2+ on gland activity. One of these effects is the demonstrated requirement of 0.1 mM extracellular Ca2+ for allatostatin inhibition of JH I synthesis by larval CA.
Mol Cell Endocrinol 1992 Apr
PMID:Manipulation of intracellular calcium affects in vitro juvenile hormone synthesis by larval corpora allata of Manduca sexta. 137 73

Calcium-induced calcium release (CICR) pools have been demonstrated in brain and heart microsomes biochemically and autoradiographically by the sensitivity of 45Ca2+ accumulation to Mg2+, ATP, ruthenium red, caffeine, and tetracaine. The CICR pool colocalizes with [3H]ryanodine binding sites, supporting the notion that [3H]ryanodine labels CICR pools. Sites of CICR pools in the brain contrast with those of inositol 1,4,5-trisphosphate (IP3)-sensitive Ca2+ pools with reciprocal localizations between the two Ca2+ pools in several structures. Thus, in the hippocampus CA-1 is enriched in IP3-sensitive Ca2+ pools, whereas CICR pools are highest in CA-3 and the dentate gyrus. The corpus striatum and cerebellum are enriched in IP3 pools, whereas the medial septum and olfactory bulb have high CICR densities. In cardiac tissue, CICR is localized to atrial and ventricular muscle, whereas IP3 pools are concentrated in coronary vessels and cardiac conduction fibers. The reciprocal enrichment of IP3 and CICR Ca2+ pools implies differential regulation of Ca2+ hemostasis in these tissues.
Mol Biol Cell 1992 Jun
PMID:Calcium pools mobilized by calcium or inositol 1,4,5-trisphosphate are differentially localized in rat heart and brain. 137 55

1,1,1-Trichloroethane is a widely used solvent that is annually linked to several cases of sudden death following accidental exposure or abuse. Sudden death is believed to be due to ventricular fibrillation or myocardial depression. The purpose of this study was to investigate the mechanism of myocardial depression by assessing the influence of 1,1,1-trichloroethane on intracellular Ca transients in single neonatal rat ventricular myocytes using spectrofluorometric analysis of fura-2-Ca binding. Cells were exposed to 1,1,1-trichloroethane in Hanks' balanced salt solution aliquoted as a 0.2% DMSO solution by a single pass suffusion in an environmentally controlled chamber. 1,1,1-Trichloroethane (0.25 mM-8 mM) reduced the height of electrically (1 Hz, 60 V, 10 ms) induced Ca transients concentration dependently and reversibly to a maximum of about 50% with no effect on diastolic Ca concentration. Video motion analysis revealed an inhibition of contractility in the same concentration range. 1,1,1-Trichloroethane inhibited cytosolic Ca increase in response to KCl-induced (90 mM) depolarizations and further decreased the limited Ca transients in ryanodine (1 microM) pretreated myocytes. Increased external Ca (5 mM) antagonized the effect of 0.5 mM 1,1,1-trichloroethane on the Ca transients. 1,1,1-Trichloroethane reduced the caffeine (10 mM) releasable Ca pool in myocytes. These results show that 1,1,1-trichloroethane inhibits Ca mobilization during excitation-contraction coupling in ventricular myocytes. An inhibitory action on the influx of extracellular Ca as well as on sarcoplasmic reticulum Ca release and sequestration is likely to be responsible for this action.
J Mol Cell Cardiol 1992 Jun
PMID:Calcium transients in isolated cardiac myocytes are altered by 1,1,1-trichloroethane. 151 78


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