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Query: UNIPROT:P06889 (Mol)
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Previous studies have shown that the muscle fibers that survive on the epicardial surface of a 5- or 14-day-old infarct in canine hearts have reduced or absent plateau phase during repolarization. Since the absence of a plateau phase could be related to a decrease in the slow inward current, we determined whether norepinephrine (NE) (3.13 x 10(-5) M) or caffeine (2.5 to 5.0 mM) restored the reduced plateau phase of action potentials of fibers from the 5- to 14-day infarct (4 mM K+). In addition, we compared the slow inward current-mediated slow response action potentials induced by NE or caffeine in K+ depolarized fibers from the 5- and 14-day infarcts to those induced in control fibers. Our results show that NE and caffeine had little or no significant effects on repolarization or the plateau area of action potentials of fibers from infarcted preparations. In addition, NE and caffeine both induced slow response action potentials in normal fibers, but in some fibers from infarcts, these agents failed to elicit slow responses. In other fibers from infarcts, NE and caffeine induced slow response action potentials but they had reduced mean areas when compared to the control potentials. In conclusion, the alteration and absence of slow responses in fibers from infarcted preparations suggest that there may be a chronic abnormality in the slow Ca current channel in fibers from the 5- and 14-day infarct.
J Mol Cell Cardiol 1988 Jun
PMID:Action potentials of cardiac muscle in healing infarcts: response to norepinephrine and caffeine. 285 Oct 55

We examined two sets of genes expressed early in the developmental cycle of Dictyostelium discoideum that appear to be regulated by cyclic AMP (cAMP). The transcripts of both sets of genes were not detectable in vegetative cells. During normal development on filter pads, RNA complementary to these genes could be detected at about 2 h, peaked around 6 to 8 h, and decreased gradually thereafter. Expression of these genes upon starvation in shaking culture was stimulated by pulsing the cells with nanomolar levels of cAMP, a condition that mimics the in vivo pulsing during normal aggregation. Expression was inhibited by caffeine or by continuous levels of cAMP, a condition found later in development when in vivo expression of these genes decreased. The inhibition of caffeine could be overcome by pulsing cells with cAMP. These results suggest that the expression is mediated via the cell surface cAMP receptor, but does not require a rise in intracellular cAMP. mRNA from a gene of the second class was induced upon starvation, peaked by 2.5 h of development, and then declined. In contrast to the other genes, its expression was maintained by continuous levels of cAMP and repressed by cAMP pulses. These and other results on a number of classes of developmentally regulated genes indicates that changing levels of cAMP, acting via the cell surface cAMP receptor, are involved in controlling these groups of genes. We also examined the structure and partial sequence of the cAMP pulse-induced genes. The two tandemly duplicated M3 genes were almost continuously homologous over the sequenced portion of the protein-coding region except for a region near the N-terminal end. The two M3 genes had regions of homology in the 5' flanking sequence and showed slight homology to the same regions in gene D2, another cAMP pulse-induced gene. D2 showed extremely significant homology over its entire sequenced length to an acetylcholinesterase. The results presented here and by others suggest that expression of many early genes in D. discoideum is regulated via the cell surface cAMP receptor. We expect that many of these genes may play essential roles in early Dictyostelium development and could code for elements of the cAMP signal transduction pathway involved in aggregation.
Mol Cell Biol 1987 Jan
PMID:Cyclic AMP regulation of early gene expression in Dictyostelium discoideum: mediation via the cell surface cyclic AMP receptor. 303 75

Phosphorylase ab hybrid was demonstrated in perfused rat hearts and during the in vitro conversion of purified rat heart phosphorylase b. Phosphorylase ab hybrid was determined in rat heart extracts by the activating effect of AMP in the presence of caffeine. These results were confirmed by the quantitative determination of incorporated 32P in vitro and through the characteristic inhibition of ab hybrid by glucose-6-phosphate. As shown by our results, in aerobically perfused control hearts only the ab hybrid represents the active form of phosphorylase, its activity reaching about 20% of the total. In response to isoproterenol (5-1000 ng), the amount of ab hybrid rose to about 30-40%, preceding the rise of the a form, which increased in a dose-dependent manner up to 45% of the total. The great sensitivity of the ab form to AMP activation and glucose-6-phosphate inhibition supports its physiological significance in heart under in vivo conditions as well. Our results strongly suggest that the activity ratio -AMP/ + AMP reflects rather the percentage ratio of phosphorylated subunits than that of the activated (partially or totally phosphorylated) phosphorylase molecules.
Mol Cell Biochem 1986 Feb
PMID:Formation of partially phosphorylated phosphorylase in isoproterenol stimulated rat hearts. 308 38

Intracellular Ca2+ stores were studied in sympathetic neurons grown in primary culture from the superior cervical ganglion of the rat. The [Ca2+]i was measured in single cells using the fluorescent Ca2+ indicator fura-2 and a sensitive microfluorimeter. Superfusion of the cells with 10 mM caffeine elicited a rapid and transient increase in [Ca2+]i in the absence of extracellular Ca2+, indicating the presence of a caffeine-sensitive intracellular Ca2+ storage site. After depletion of the store by mobilization of Ca2+ with caffeine, it could be refilled by elevating [Ca2+]i, allowing multiple caffeine-induced [Ca2+]i transients to be elicited from a single neuron. Ryanodine (1 microM), an alkaloid that promotes Ca2+ release from the sarcoplasmic reticulum, was an effective inhibitor of the caffeine-induced [Ca2+]i transients in sympathetic neurons. Exposure to ryanodine in the presence of caffeine was required to produce a subsequent inhibition of the caffeine-induced response, suggesting a "use-dependent" inhibition that may result from depletion of the Ca2+ stores. In contrast, dantrolene Na (10 microM), an agent known to interfere with Ca2+ release from the sarcoplasmic reticulum, also blocked the caffeine-induced [Ca2+]i transients, but in a time-dependent rather than a use-dependent manner. Electrophysiological measurements using the whole cell version of the patch-clamp technique were made simultaneously with [Ca2+]i microfluorimetric recordings. The magnitude of the [Ca2+]i transients elicited by step depolarizations closely paralleled the magnitude of Ca2+ influx via voltage-sensitive Ca2+ channels, regardless of whether the magnitude of the Ca2+ current was modified by varying the test pulse duration or potential. The relationship between the magnitude of Ca2+ influx and the resulting increase in [Ca2+]i saturated at large Ca2+ influxes resulting from long depolarizations, consistent with the activation of a large capacity, low affinity [Ca2+]i buffering mechanism. Caffeine (10 mM) and ryanodine (10 microM), applied singly or together, produced a small and variable decrease in the [Ca2+]i transient resulting from cell depolarization using the whole-cell patch-clamp technique. We conclude that mammalian sympathetic neurons possess intracellular Ca2+ stores with pharmacological characteristics that closely resemble those found in muscle but that these are relatively small and produce little amplification of [Ca2+]i transients resulting from Ca2+ influx through voltage-sensitive Ca2+ channels.
Mol Pharmacol 1988 Nov
PMID:The role of caffeine-sensitive calcium stores in the regulation of the intracellular free calcium concentration in rat sympathetic neurons in vitro. 319 57

Developed twitch tension and action potentials were recorded in rabbit ventricular muscle in physiological saline at 30 degrees C stimulated at 0.5 Hz. Addition of 5 microM nifedipine to block Ca entry via Ca channels almost abolished twitches (to 2.5 +/- 0.7%, S.E.M., n = 10 of control). This suggests that under normal conditions Ca entry via Na-Ca exchange is insufficient to activate contractions. However, when muscles are first exposed to 4 microM acetylstrophanthidin to elevate [Na]i the same exposure to nifedipine only partially suppresses twitches (to 59 +/- 12% of the original control). This suggests that when [Na]i is elevated, Ca entry via the Na-Ca exchange may be adequate to partially activate contraction. From this result it is not clear whether Ca entry via Na-Ca exchange is sufficient to activate contraction directly or whether sarcoplasmic reticulum (SR) Ca release is required. When these experiments were carried out in the presence of 5 to 10 mM caffeine or 100 nM ryanodine similar results were obtained. That is, nifedipine still abolished contractions in the presence of caffeine or ryanodine (to 3.8 +/- 0.3% and 1.3 +/- 0.4%, respectively), but only partially inhibited contractions in the presence of caffeine + acetylstrophanthidin (to 21 +/- 5%) or ryanodine + acetylstrophanthidin (10 +/- 2%). Thus, it appears that even in the absence of a functional SR and with Ca current blocked, Na-Ca exchange might bring sufficient Ca into the cell to activate appreciable contractions, but only when [Na]i is elevated. Action potential duration is decreased by nifedipine and acetylstrophanthidin and is further decreased when nifedipine is added on top of acetylstrophanthidin. If this Ca entry is by an electrogenic 3 Na: 1 Ca exchange, Ca entry will be favored at more positive membrane potentials. If the action potential were not so abbreviated with these drugs, Na-Ca exchange might bring in more Ca and activate additional tension.
J Mol Cell Cardiol 1988 May
PMID:Can Ca entry via Na-Ca exchange directly activate cardiac muscle contraction? 321 Feb 49

Nine coffee preparations, four caffeinated instant brands, three caffeinated drip coffees, and two decaffeinated coffees, one of which was an instant brand, were evaluated for mutagenicity by the Ames assay using Salmonella typhimurium TA100, TA102, and TA104. All the coffees contained direct-acting mutagens, which reverted the three strains. The inclusion of a rat microsomal enzyme preparation reduced the mutagenic response of the three strains in the presence of some of the coffee samples. Both glyoxal and methylglyoxal, 1,2-dicarbonyls found in the coffees were mutagenic. The concentration of glyoxal, methyglyoxal, diacetyl, and guiacol were measured by gas chromatography/mass spectrometry. Caffeine, furfural, and 5-methylfurfural concentrations were determined by high performance liquid chromatography. Although lower concentrations of methyglyoxal were found in the drip caffeinated coffees, the mutagenic potency of these preparations was higher than the instant coffees on a weight basis especially when TA104 was the indicator organism. Our findings agree with those of other workers who have shown that carbonyl compounds, which were present in all the brands tested, are partially responsible for the mutagenic response of coffee but that additional mutagens are also present.
Environ Mol Mutagen 1988
PMID:Comparative mutagenicity of nine brands of coffee to Salmonella typhimurium TA100, TA102, and TA104. 327 96

Delayed afterdepolarizations and triggered activity occur in atrial cells of the canine coronary sinus in response to catecholamines. We studied the properties of the membrane current that causes the afterdepolarizations with the two-microelectrode voltage clamp technique in small preparations (about 0.5 x 1 mm). At a holding potential of -50 mV a transient inward current (TI) occurred after repolarization from a depolarizing step to between -40 and -20 mV in the absence of catecholamines. When the depolarizing pulse was made more positive or its duration increased the amplitude of the TI current increased and it reached peak amplitude faster. The current-voltage relationship of the TI current was studied by changing the voltage to which the membrane was repolarized after a depolarizing clamp pulse of fixed amplitude and duration. At repolarization levels positive to -30 mV there were current fluctuations without a distinct TI current. As the repolarization voltage was made more negative, a TI current occurred and its time to peak increased monotonically. The TI current amplitude increased and reached a maximum amplitude at around -60 to -70 mV, and then declined at more negative repolarization voltages. Norepinephrine increased the TI current while simultaneously augmenting the slow inward current. Elevating [Ca]0 increased the TI current amplitude. Caffeine (2 mM) increased the TI current amplitude, while caffeine (4 mM) increased and then decreased the current amplitude. The dependence of the TI current on the voltage and duration of the activating depolarizing step in these atrial cells are qualitatively similar to those of the TI current associated with digitalis toxicity in Purkinje fibers and ventricular muscle, although there are some quantitative differences. There is no distinct TI reversal in these atrial cells, similar to TI in ventricular muscle but dissimilar to TI in Purkinje fibers.
J Mol Cell Cardiol 1987 Nov
PMID:Characteristics of a transient inward current that causes delayed afterdepolarizations in atrial cells of the canine coronary sinus. 343 61

The association of a protein kinase with cytoplasmic non-polysomal messenger ribonucleoproteins is demonstrated by chromatography on oligo(dT)-cellulose and sucrose gradient centrifugation. The cAMP-independent enzyme is inhibited by caffeine and poly(L)-glutamic acid and is classified as a casein kinase II. Among the exogenous proteins initiation factor eIF2 is the best substrate and is 7.8 times more efficiently phosphorylated than casein. Endogenous mRNP protein substrates have a Mr of 125 000, 65 000, 38 000, 26 000 and 23 500. The main phosphate acceptor is the Mr 38 000 poly(A)-binding protein. Dephosphorylation of the poly(A)-binding protein by protein phosphatases decreases its RNA binding property. The effect of phosphorylation-dephosphorylation of mRNP proteins on the initiation of protein synthesis is discussed.
Mol Biol Rep 1986
PMID:Identification of the substrates of the casein kinase II associated with non-polysomal messenger ribonucleoproteins of A. salina cryptobiotic embryos. 346 Dec 61

Studies were made on the genetic consequences of methotrexate-directed thymidylate stress, focusing attention on a human thymidylate synthase gene that was introduced as a heterologous genetic marker into mouse thymidylate synthase-negative mutant cells. Thymidylate stress induced thymidylate synthase-negative segregants with concomitant loss of human thymidylate synthase activity with frequencies 1 to 2 orders of magnitude higher than the uninduced spontaneous level in some but not all transformant lines. Induction of the segregants was suppressed almost completely by cycloheximide and partially by caffeine. Thymidylate stress did not, however, induce mutations, as determined by measuring resistance to ouabain or 6-thioguanine. Thymidylate synthase-negative segregants were also induced by other means such as bromodeoxyuridine treatment and X-ray irradiation. In each of the synthase-negative segregants induced by thymidylate stress, a DNA segment including almost the whole coding region of the transferred human thymidylate synthase gene was deleted in a very specific manner, as shown by Southern blot analysis with a human Alu sequence and a human thymidylate synthase cDNA as probes. In the segregants that emerged spontaneously at low frequency, the entire transferred genetic marker was lost. In the segregants induced by X-ray irradiation, structural alterations of the genetic marker were random. These results show that thymidylate stress is a physiological factor that provokes the instability of this exogenously incorporated DNA in some specific manner and produces nonrandom genetic recombination in mammalian cells.
Mol Cell Biol 1986 Oct
PMID:Induction, by thymidylate stress, of genetic recombination as evidenced by deletion of a transferred genetic marker in mouse FM3A cells. 379 89

The effects of positive inotropic agents on the amplitude and time course of the light signal and corresponding tension response were studied in cat and human working myocardium microinjected with the bioluminescent Ca2+ indicator aequorin. Distinctive patterns of light and tension responses were identified that are consistent with known actions of the various agents on the release of Ca2+ from intracellular stores, rate of uptake of Ca2+ by the sarcoplasmic reticulum and sensitivity of the myofilaments to Ca2+. In common with most other inotropic drugs, the cardiotonic steroid, acetylstrophanthidin, in doses of 4 X 10(-7) to 2 X 10(-6)M increases the amount of Ca2+ available for excitation-contraction coupling in the heart. However, in contrast to most other agents, acetylstrophanthidin does not affect the time course of the calcium transient. In common with changes in [Ca2+]o, acetylstrophanthidin does not alter the relationship between the amplitude of the aequorin light signal and developed tension, which, in contrast to caffeine and isoproterenol, indicates that the increase in tension is fully accounted for by the increase in systolic free calcium. These findings suggest that the cardiotonic steroids increase loading of intracellular calcium stores without affecting the kinetics of subcellular handling of Ca2+. In doses of 8 X 10(-7) to 2 X 10(-6)M, acetylstrophanthidin produces a calcium-overload state characterized by 'after-contractions' and 'after-glimmers' that are associated with the development of automatic and triggerable dysrhythmias. These studies provide direct evidence that the inotropic and toxic effects of digitalis on animal and human working myocardium are produced by changes in intracellular Ca2+.
J Mol Cell Cardiol 1985 Nov
PMID:The effects of digitalis on intracellular calcium transients in mammalian working myocardium as detected with aequorin. 390 93


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