Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0848283 (rundown)
 502 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thapsigargin stimulates an increase of cytosolic free Ca2+ concentration [( Ca2+]c) in, and 45Ca2+ efflux from, a clone of GH4C1 pituitary cells. This increase in [Ca2+]c was followed by a lower sustained elevation of [Ca2+]c, which required the presence of extracellular Ca2+, and was not inhibited by a Ca2(+)-channel blocker, nimodipine. Thapsigargin had no effect on inositol phosphate generation. We used thyrotropin-releasing hormone (TRH) to mobilize Ca2+ from an InsP3-sensitive store. Pretreatment with thapsigargin blocked the ability of TRH to cause a transient increase in both [Ca2+]c and 45Ca2+ efflux. The block of TRH-induced Ca2+ mobilization was not caused by a block at the receptor level, because TRH stimulation of InsP3 was not affected by thapsigargin. Rundown of the TRH-releasable store by Ca2(+)-induced Ca2+ release does not appear to account for the action of thapsigargin on the TRH-induced spike in [Ca2+]c, because BAY K 8644, which causes a sustained rise in [Ca2+]c, did not block Ca2+ release caused by TRH. In addition, caffeine, which releases Ca2+ from intracellular stores in other cell types, caused an increase in [Ca2+]c in GH4C1 cells, but had no effect on a subsequent spike in [Ca2+]c induced by TRH or thapsigargin. TRH caused a substantial decrease in the amount of intracellular Ca2+ released by thapsigargin. We conclude that in GH4C1 cells thapsigargin actively discharges an InsP3-releasable pool of Ca2+ and that this mechanism alone causes the block of the TRH-induced increase in [Ca2+]c.
 ...
PMID:Thapsigargin, but not caffeine, blocks the ability of thyrotropin-releasing hormone to release Ca2+ from an intracellular store in GH4C1 pituitary cells. 169 7

1. The effects of aluminium on membrane ionic currents were studied in single cardiac myocytes. Most of the work was done on frog atrial cells, but some experiments were also carried out on single cells isolated from rabbit ventricles and atria. 2. The effects of aluminium on the force of contraction of frog atrial trabeculae were also investigated. 3. Aluminium was prepared from AlCl3 as a stock 0.5 M solution which has a pH of 3.5. Before each experiment, this solution was added to the control solution, to give a final concentration of 20-100 micrograms ml-1 aluminium (0.75-3.75 mM AlCl3). The solutions were brought to a pH of 7.4 or 7.6. at which they consist of a mixture of amorphous aluminium hydroxides and a very small amount of soluble ionic aluminium complexes: free aluminium cations (less than 10 pM), aluminohydroxide anions (less than 8 microM). The addition of this suspension reduced the peak inward calcium currents in single rabbit atrial and ventricular cells and in frog atrial cells. In the latter, the peak current was reduced (at + 10 mV) to 45% of control (mean of 9 cells). This effect was reversible upon washout, and was obtained at all membrane potentials, with no shift of the calcium current voltage relationship along the voltage axis. 4. Aluminium also reduced the time-dependent potassium current IK. This reduction was observed at all membrane potentials. For example, at + 10 mV, the mean reduction of IK (n = 9) was to 69% of the control amplitude. This effect, which was very difficult to reverse, was not due to IK rundown. The fully activated current-voltage relationships (obtained by standard 'tail' analysis) showed that the effect of aluminium was due mainly to a decrease in conductance and not to a shift in the activation range of IK. The mean voltage of half activation was shifted by 8 mV in the depolarizing direction (n = 5). 5. The background potassium current IK1 was also slightly but consistently changed in a complex fashion, with an outward shift at membrane potentials positive to -60 mV. For example, at a membrane potential of -40mV, the mean shift was by 22 + 4pA. At more negative potentials, there was an inward shift in the current amplitudes. For example, for steps to -I00 mV the current elicited was larger (more inward) by 53 pA (mean value, n = 10). The reversal potential was slightly shifted (<10 mV) in the hyperpolarizing direction. 6. The force of contraction of frog atrial trabeculae was altered by aluminium in a complex manner, which showed marked seasonal variation. During most of the year, 50-100,ug ml-1 aluminium caused a biphasic change, with an early small and consistent decrease, followed by a large increase in twitch amplitude. For a short period corresponding to the (local) winter months the sensitivity to aluminium was greatly enhanced. Aluminium lOOupgml-1 totally abolished contraction (n = 5), while a lower concentration (20,ug ml- 1) produced a sustained reduction in the force of contraction. Similar biphasic and seasonal responses have been reported to be induced by lanthanum. 7. The biphasic changes in twitch amplitude were independent of the transmembrane sodium gradient. Aluminium produced the same effects when 90% of the extracellular sodium was replaced by lithium. Caffeine (5 mM) attenuated or even inverted the positive inotropic effect of aluminium. These results imply that aluminium alters the release of calcium from intracellular, caffeine-sensitive stores. This could be effected either by augmenting the amount released during each activation, and/or by increasing the loading of stores prior to release.
 ...
PMID:Effects of aluminium on electrical and mechanical properties of frog atrial muscle. 201 25

The role of prejunctional purinoceptors (P1-subtype) in the control of ATP-release from inhibitory motoneurons was investigated electrophysiologically, by studying fast purinergic inhibitory junction potentials (IJPs) in guinea-pig ileal circular muscle. Pressure ejections of adenosine and ATP (but not of alpha,beta-methylene ATP) onto circular muscle depressed the amplitude of fast IJPs, indicating the presence of prejunctional P1-purinoceptors. An adenosine (A1/2)-receptor antagonist, theophylline (10(-8)-10(-4) M), increased the amplitude of fast IJPs in a dose-related manner (EC50 = 17.5 microM), suggesting the existence of a basal 'adenosine tone' that regulated ATP-release from ileal motoneurons. However, three methylxanthine derivatives, caffeine (10(-8)-10(-4) M), 3-isobutyl-1-methylxanthine (IBMX; 10(-8)-10(-4) M) and the potent A1-receptor antagonist 1,3-dipropyl-8-(2-amino-4-chlorophenyl)-xanthine (DPCPX; 10(-8)-10(-4) M), failed to potentiate fast IJPs and placed in doubt the existence of this inhibitory adenosine tone. Caffeine and IBMX, but not DCPCX, hyperpolarised ileal circular muscle in a dose-related manner and reduced IJP-amplitude; DPCPX did not alter the amplitude of IJPs. The non-specific inhibitor of phosphodiesterases, Ro-20-1724 (5 x 10(-7)-5 x 10(-5) M), increased the amplitude of fast IJPs, mimicking the actions of theophylline. To this extent, facilitation of inhibitory transmission appeared to involve phosphodiesterase inhibition and modification of intra-axonal cAMP levels and phosphorylation of intra-axonal protein kinases. The phenomenon of IJP rundown, presumed to be a manifestation of prejunctional autoinhibition, was studied using theophylline and DPCPX as A1-receptor antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Prejunctional autoinhibition of purinergic transmission in circular muscle of guinea-pig ileum; a mechanism distinct from P1-purinoceptor activation. 802 18

1. The role of cyclic ADP ribose and ryanodine receptors in the inhibition of the M-like current (IK(M,ng)) by acetylcholine was investigated in m1 muscarinic receptor-transformed mouse neuroblastoma-rat glioma hybrid (NG108-15) cells using patch-clamp techniques and calcium microfluorimetry. 2. Acetylcholine (1-100 microM) decreased IK(M,ng) by up to 55 %. Application, via the patch pipette, of the cyclic ADP ribose antagonists 8-amino-cyclic ADP ribose (10-100 microM) and 8-bromo-cyclic ADP ribose (100-1000 microM) reduced this inhibition of IK(M,ng) in a concentration-dependent manner. The half-maximal inhibition concentrations for 8-amino- cyclic ADP ribose and 8-bromo-cyclic ADP ribose were around 40 microM and 1 mM, respectively. 3. Neither of the cyclic ADP ribose antagonists altered the amplitude of IK(M,ng) per se, or the incidence of the concurrent Ca2+-activated K+ current (IIK(Ca)) activation, also mediated by acetylcholine. 4. The ryanodine receptor modulators ryanodine (1-10 microM) and Ruthenium Red (10 microM) did not alter IK(M,ng) amplitude or IK(M,ng) inhibition mediated by acetylcholine. There was a statistically significant increase in the proportion of cells showing outward currents in the presence of Ruthenium Red. 5. Intracellular calcium levels measured with fura-2 microfluorimetry were increased with low concentrations of ryanodine (1 microM), more consistently with caffeine (10 mM), and in almost every case with both bradykinin (300 nM) and acetylcholine (100 microM). Caffeine-, but not bradykinin-evoked responses were abolished by preincubation with ryanodine (10 microM). 6. The fast 'rundown rate' of the M-current recorded in rat superior cervical ganglion cells under whole-cell conditions precluded an investigation of the effects of intracellular dialysis of cyclic ADP ribose. However, when cyclic ADP ribose (5 microM) was applied directly to the cytoplasmic face of inside-out membrane patches excised from rat superior cervical ganglion cells containing M-channels, it had no effect on the main parameters of single channel activity (conductance, mean open time or frequency of opening). 7. These results indicate that cyclic ADP ribose acts on a specific intracellular site to mediate IK(M,ng) inhibition. However, unlike previously established effects of cyclic ADP ribose, the ryanodine receptor is not required, suggesting that another molecular target may be involved. Studies at the single channel level indicate that cyclic ADP ribose may not act directly on the M-channels in inside-out patches.
 ...
PMID:The role of ryanodine receptors in the cyclic ADP ribose modulation of the M-like current in rodent m1 muscarinic receptor-transformed NG108-15 cells. 1043 36

Ca(2+)-dependent Cl(-) (Cl(-)(Ca)) channels and their regulation by intracellular Ca(2+) concentration ([Ca(2+)](i)) and nitric oxide (NO) were characterized in mouse and rabbit aortic smooth muscle cells (SMC) using patch clamp and fura 2 imaging. Single channels (1. 8 pS) and whole cell Cl(-)(Ca) currents were activated by caffeine-induced Ca(2+) release. Single Cl(-)(Ca) channels were also activated by >/=200 nM Ca(2+) in inside-out membrane patches and remained active for >5 min in </=1 microM Ca(2+) but showed rapid rundown in 2 mM Ca(2+). Authentic NO or S-nitroso-N-acetylpenicillamine (SNAP) did not affect their activation or rundown in inside-out patches. In the whole cell, SNAP (100 microM) and 8-(4-chlorophenylthio)-guanosine 3',5'-cyclic monophosphate (50 microM) did not affect Cl(-)(Ca) current, but at a higher concentration SNAP (1 mM) induced a sustained [Ca(2+)](i) rise, accompanied by a dramatic decrease in caffeine-induced Ca(2+) release and Cl(-)(Ca) current. These results indicate that 1) mouse and rabbit aortic SMC possess 1.8-pS Cl(-)(Ca) channels that are activated by Ca(2+) release from the stores, 2) both activation and rundown of single Cl(-)(Ca) channels depend on [Ca(2+)](i), and 3) NO does not affect Cl(-)(Ca) channels directly or via cGMP but can inhibit their activation indirectly by decreasing Ca(2+) release from the stores.
 ...
PMID:Ca(2+)-dependent Cl(-) channels in mouse and rabbit aortic smooth muscle cells: regulation by intracellular Ca(2+) and NO. 1056 26

In this study, the relationship between intracellular calcium stores and depolarization-evoked stimulation was examined in bovine chromaffin cells, using changes in membrane capacitance to monitor both exocytosis and endocytosis. Cells were voltage-clamped using the perforated whole-cell patch configuration to minimize alterations in intracellular constituents. Control cells exhibited reproducible secretory responses each time the cell was stimulated. However, the same stimulation protocol elicited progressively smaller secretory responses in cells where their intracellular calcium store was emptied by thapsigargin. Transient elevation of the intracellular calcium concentration with a brief histamine treatment enhanced subsequent secretory responses in control but not in thapsigargin-treated cells. A series of depolarizations to -20 mV, which allowed small amounts of Ca(2+) influx but which by itself did not trigger catecholamine secretion, enhanced subsequent exocytosis in both control and thapsigargin-treated cells. Caffeine-pretreated cells exhibited a rundown in the secretory response that was similar to that produced by thapsigargin. These results suggest that brief elevations of [Ca(2+)](i) could enhance subsequent secretory responses. In addition, the data suggest that intracellular calcium stores are vital for the maintenance of exocytosis during repetitive stimulation.
 ...
PMID:Rundown of secretion after depletion of intracellular calcium stores in bovine adrenal chromaffin cells. 1093 95

Ageing is generally associated with a decline in skeletal muscle mass and strength, and a slowing of muscle contraction, factors that impact upon the quality of life for the elderly. Alterations in Ca2+ handling are thought to contribute to these age-related changes in muscle contractility, yet the effects of ageing on sarcoplasmic reticulum (SR) Ca2+ handling and the Ca2+ transport system remain unresolved. We used mechanically skinned single fibres from the fast twitch extensor digitorum longus (EDL) muscles from young (4-month-old) and old (27- to 28-month-old) mice to test the hypothesis that the age-related changes in skeletal muscle contractility, especially the slower rate of contraction, are due to changes intrinsic to the muscle fibres. There were no age-related differences in the peak height of depolarization-induced contractile response (DICR) or the number of DICRs elicited before rundown (DICR < 50 % of initial). The time taken to reach peak DICR (TPDICR) was approximately12 % slower in single muscle fibres from old compared with young mice (P < 0.05). The rate of relaxation following DICR was not different in young and old mice. Examination of SR function demonstrated that SR Ca2+ reloading in Ca2+ -depleted skinned fibres was not different in young and old mice, nor was there any age-related difference in Ca2+ leak from the SR. However, low [caffeine] contracture in fibres from old mice was only half of that observed in fibres from young mice (P < 0.05), indicating a lower sensitivity of the SR Ca2+ release channel (CRC) to caffeine. We found no difference in maximum Ca2+ -activated force (P(o)) or specific force (sP(o); P(o) corrected for cross-sectional area) in EDL muscle fibres from young and old mice. Impaired excitation-contraction (E-C) coupling and a decrease in SR CRC function are mechanisms which are likely to contribute to the overall slowing of muscle contraction with age.
 ...
PMID:Excitation-contraction coupling and sarcoplasmic reticulum function in mechanically skinned fibres from fast skeletal muscles of aged mice. 1218 Dec 89

A calcium dependent-chloride current (I(ni)) was recorded in Xenopus oocytes injected with total RNA from chicory leaf tissues, following depolarization from -35 to +60 mV. However, the signal transduction mechanism mediating I(ni) is unknown. The development of this current was mimicked by intracellular injection of the second messenger InsP(3) in control (non-injected) oocytes. Moreover, InsP(3) injection after I(ni) rundown did not reinitiate the current. The same phenomenon was observed following a second injection into control oocytes. Measurement of InsP(3) production in injected oocytes showed a net increase in the InsP(3) level on depolarization. Moreover, extracellular application of caffeine (5 mM) significantly reduced the number of oocytes displaying I(ni). Also, extracellular application of U-73122, a potent PLC inhibitor, clearly reduced the occurrence of I(ni). These data provide the first evidence that the calcium homeostasis mechanism induced by heterologous expression of total RNA from chicory leaves involves the InsP(3) signaling pathway.
 ...
PMID:InsP(3)-mediated calcium release induced by heterologous expression of total chicory Leaf RNA. 1256 27

Dystrophin is absent in muscle fibers of patients with Duchenne muscular dystrophy (DMD) and in muscle fibers from the mdx mouse, an animal model of DMD. Disrupted excitation-contraction (E-C) coupling has been postulated to be a functional consequence of the lack of dystrophin, although the evidence for this is not entirely clear. We used mechanically skinned fibers (with a sealed transverse tubular system) prepared from fast extensor digitorum longus muscles of wild-type control and dystrophic mdx mice to test the hypothesis that dystrophin deficiency would affect the depolarization-induced contractile response (DICR) and sarcoplasmic reticulum (SR) function. DICR was similar in muscle fibers from mdx and control mice, indicating normal voltage regulation of Ca2+ release. Nevertheless, rundown of DICR (<50% of initial) was reached more rapidly in fibers from mdx than control mice [control: 32 +/- 5 depolarizations (n = 14 fibers) vs. mdx: 18 +/- 1 depolarizations (n = 7) before rundown, P < 0.05]. The repriming rate for DICRs was decreased in fibers from mdx mice, with lower submaximal DICR observed after 5, 10, and 20 s of repriming compared with fibers from control mice (P < 0.05). SR Ca2+ reloading was not different in fibers from control and mdx mice, and no difference was observed in SR Ca2+ leak. Caffeine (2-7 mM)-induced contraction was diminished in fibers from mdx mice compared with control (P < 0.05), indicating depressed SR Ca2+ release channel activity. Our findings indicate that fast fibers from mdx mice exhibit some impairment in the events mediating E-C coupling and SR Ca2+ release channel activity.
 ...
PMID:Depolarization-induced contraction and SR function in mechanically skinned muscle fibers from dystrophic mdx mice. 1272 37

The role of adenosine triphosphate (ATP) as a neurotransmitter and extracellular diffusible messenger has recently received considerable attention because of its possible participation in the regulation of synaptic plasticity. However, the possible contribution of extracellular ATP in maintaining and regulating synaptic efficacy during intracellular ATP depletion is understudied. We tested the effects of extracellular ATP on excitatory postsynaptic currents (EPSCs) evoked in CA1 pyramidal neurons by Schaffer collateral stimulation. In the absence of intracellular ATP, EPSC rundown was neutralized when a low concentration of ATP (1 microm) was added to the extracellular solution. Adenosine and ATP analogues did not prevent the EPSC rundown. The P(2) antagonists piridoxal-5'-phosphate-azophenyl 2',4'-disulphonate (PPADS) and reactive blue-2, and the P(1) adenosine receptor antagonist 8-cyclopentyltheophylline (CPT) had no detectable effects in cells depleted of ATP. However, the protective action of extracellular ATP on synaptic efficacy was blocked by extracellular application of the protein kinase inhibitors K252b and staurosporine. In contrast, K252b and staurosporine per se did not interfere with synaptic transmission in ATP loaded cells. Without intracellular ATP, bath-applied caffeine induced a transient (< 35 min) EPSC potentiation that was transformed into a persistent long-term potentiation (> 80 min) when 1 microm ATP was added extracellularly. An increased probability of transmitter release paralleled the long-term potentiation induced by caffeine, suggesting that it originated presynaptically. Therefore, we conclude that extracellular ATP may operate to maintain and regulate synaptic efficacy and plasticity in conditions of abnormal intracellular ATP depletion by phosphorylation of a surface protein substrate via activation of ecto-protein kinases.
 ...
PMID:Stabilizing effects of extracellular ATP on synaptic efficacy and plasticity in hippocampal pyramidal neurons. 1578


1