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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Ca2+-ryanodine receptor complex is a functional unit at the terminal cisternae (TC) of the sarcoplasmic reticulum (SR) whose proteins comprise the Ca2+ release channels which may be involved in excitation-contraction coupling. Ca2+, Mg2+, caffeine, and adenine nucleotides, but not inositol 1,4,5-trisphosphate, may exert their inotropic effects on skeletal muscle SR by direct allosteric modulation of the [3H]ryanodine-binding site. Micromolar Ca2+ is primarily responsible for activating [3H]ryanodine binding by regulating receptor site density, affinity, and cooperativity. Mg2+ reduces the sensitivity to Ca2+ activation by directly competing with Ca2+ for the activator site. However, inhibition by Mg2+ is overcome in the presence of beta,gamma-methyleneadenosine 5'-triphosphate (AMP-PCP; 1 mM) or caffeine (20 mM). Caffeine dramatically increases the affinity of the Ca2+ activator site for Ca2+, whereas AMP-PCP or cAMP enhances the gating efficiency or the lifetime of the open state of the TC SR channel. A kinetic model is proposed for four functional domains of the Ca2+-ryanodine receptor complex: the Ca2+-regulatory domain which binds Ca2+ with microM affinity is primarily responsible for gating the Ca2+ channel of the TC SR in a cooperative manner, and is inhibited by mM Mg2+ by direct competition for the activator site which appears to contain critical sulfhydryl groups; a Ca2+-activate alkaloid binding domain in close proximity to the channel which binds ryanodine with nM affinity and rapidly occludes upon complex formation; a domain which binds caffeine with low (greater than mM) affinity and directly influences the sensitivity of the Ca2+-regulatory site; and a domain which binds adenine nucleotides with intermediate affinity (less than mM), does not require phosphorylation, and intensifies the Ca2+ signal which triggers opening of the Ca2+-release channel.
Mol Pharmacol 1987 Mar
PMID:Ca2+-activated ryanodine binding: mechanisms of sensitivity and intensity modulation by Mg2+, caffeine, and adenine nucleotides. 243 32

The methylxanthines, such as caffeine and theophylline, are an important and widely used class of drugs, which are believed to mediate many of their physiological effects by increasing intracellular concentrations of cAMP. These agents are known to inhibit phosphodiesterases and to block inhibitory A1 adenosine receptors in a competitive manner. Thus, the methylxanthines may increase cAMP accumulation by slowing its inactivation or by enhancing its production. Using a rat adipocyte membrane model we demonstrate that isobutylmethylxanthine (IBMX) induces a dose-dependent 34% increase in cAMP production above that produced by complete phosphodiesterase inhibition with papaverine. This stimulatory effect is dependent upon the inhibitory guanine nucleotide regulatory protein G1, in that inactivation of Gi by pertussis intoxication ablates IBMX-mediated stimulation of adenylate cyclase activity. Because the Gi-dependent effect of IBMX results in increased cAMP production, the mode of action is likely blockade of Gi activity. Accordingly, the capacity of GTP itself to inhibit adenylate cyclase activity is attenuated by IBMX. In contrast to Gi blockade induced by pertussis toxin, this heretofore unappreciated stimulatory mechanism is completely reversed by inhibitory receptor agonists. This mechanism of action may be responsible for certain physiological effects of methylxanthines, which are not easily explained by phosphodiesterase inhibition or antagonism of A1 adenosine receptors.
Mol Pharmacol 1988 Jul
PMID:Isobutylmethylxanthine stimulates adenylate cyclase by blocking the inhibitory regulatory protein, Gi. 245 59

The catalytic behavior and structural features of Ca2+-ATPase in the vesicles of longitudinal tubules and terminal cisternae of the sarcoplasmic reticulum isolated from rabbit skeletal muscles was analysed. pH measurements have shown under optimal conditions Ca2+-ATPase has similar catalytic behavior both in the fractions of longitudinal tubules and terminal cisternae. Under non-optimal conditions, the behavior similarity was not observed. The specific activity of the ATPase enzyme under optimal conditions was shown to be much higher in the fraction of longitudinal tubules than in the fraction of terminal cisternae. Caffeine added to both fractions had no effect on the catalytic behavior of Ca2+-ATPase. As judged from fluorescence analysis, the structure of Ca2+-ATPase of longitudinal tubules differs from that structure of terminal cisternae. In sarcoplasmic reticulum membrane, at least half of the tryptophan residues of Ca2+-ATPase was shown to be buried in the lipid bilayer. Our findings suggest that in terminal cisternae some of the Ca2+-ATPase molecules exist as an oligomeric protein and do not participate in ATP hydrolysis (named "silent" Ca2+-ATPase).
Mol Biol (Mosk)
PMID:[Comparison of the catalytic and structural properties of Ca2+-ATPase in longitudinal tubules and terminal cisternae of the sarcoplasmic reticulum]. 253 Dec 74

The ability of ionsitol 1,4,5-trisphosphate (IP3) and other inositol phosphates to induce calcium release from canine aortic sarcoplasmic reticulum vesicles was examined. Using the calcium indicator chlorotetracycline or antipyrylazo III, aortic vesicles were shown to accumulate calcium in the presence of ATP, and then release approximately 25% of the intravesicular calcium upon addition of 7 microM IP3. Inositol 2-phosphate, inositol 1,4-bisphosphate, and inositol 1,3,4,5-tetrakisphosphate did not induce calcium release from these vesicles, and GTP[gamma-S] did not affect the IP3-induced calcium release. Aortic IP3-induced calcium release was not affected by ruthenium red, but was inhibited by Mg2+ and Ca2+, and thus differs from the Mg2+-insensitive IP3-induced calcium release in platelets and the ruthenium red-sensitive IP3-induced calcium pathway in skeletal muscle sarcoplasmic reticulum. Stopped-flow analyses showed that aortic IP3-induced calcium release was much slower than the caffeine-induced calcium release from skeletal muscle sarcoplasmic reticulum. Moreover, the aortic IP3-induced calcium release was biphasic, suggestive of heterogeneity of the putative calcium channels.
J Mol Cell Cardiol 1989 Feb
PMID:Calcium release from aortic sarcoplasmic reticulum. 254 22

Various known Ca2+ channel blockers and intracellular Ca2+ antagonists have been tested for effects of inositol-1,4,5-trisphosphate (IP3)-induced Ca2+ release from isolated canine brain microsomes. In agreement with previous reports, heparin, p-chloromercuribenzoic acid, W-7, cinnarizine, flunarizine, certain local anesthetics, La3+, and Ca2+ inhibit the release of Ca2+ induced by addition of IP3. In addition, we report here pronounced inhibition of IP3-induced Ca2+ release by low levels of Cd2+, by relatively high concentrations of TMB-8, and by phytic acid. In contrast, a number of blockers of other Ca2+ channels (nifedipine, verapamil, dantrolene, dithiothreitol, and ruthenium red) have relatively little or no effect on IP3-induced Ca2+ release from brain microsomes. The relative ineffectiveness of substances that inhibit Ca2+- or caffeine-induced Ca2+ release from skeletal muscle sarcoplasmic reticulum suggests that release of Ca2+ from caffeine- and IP3-sensitive neuronal Ca2+ stores is likely to be mediated by different channels. Further evidence that different channels are involved is presented by way of demonstration of the lack of Ca2+-induced Ca2+ release from these brain microsomes and the lack of effect on sarcoplasmic reticulum caffeine-induced Ca2+ release of certain inhibitors of IP3-induced Ca2+ release used here. Among IP3-induced Ca2+ release blockers, La3+ appeared to be exceptional in its ability to stimulate microsomal Ca2+ uptake sufficiently to attenuate release of Ca2+ induced by IP3. Most blockers of IP3-induced Ca2+ release appear not to function by way of inhibiting K+ counter-ion movements (valinomycin does not reverse the inhibition) but rather by way of direct interaction with the IP3 receptor or the Ca2+ channel that mediates the IP3-induced Ca2+ release. Inhibition of [3H]IP3 binding to the microsomes by phytic acid, heparin, pyrophosphate, p-chloromercuribenzoic acid, and Ca2+ could be demonstrated but not by the other substances tested.
Mol Pharmacol 1989 Oct
PMID:Pharmacologic differentiation between inositol-1,4,5-trisphosphate-induced Ca2+ release and Ca2+- or caffeine-induced Ca2+ release from intracellular membrane systems. 255 17

Addition of quisqualate to mouse hippocampal neurons in vitro elicited two types of changes in [Ca2+]i as assessed by fura-2-based microfluorimetry. The first was a transient spike or group of oscillations and the second was a long lasting "plateau" response. The long-lasting response was abolished on removal of either Ca2+ or Na+ from the external medium or by blocking voltage-sensitive Ca2+ channels. Furthermore, the novel glutamate antagonist 6-nitro-7-cyano-quinoxaline-2,3-dione was a competitive inhibitor of this response. In contrast, none of these manipulations abolished the transient [Ca2+]i spike. Transient [Ca2+]i spikes or oscillations could also be produced by the alpha 1-adrenergic agonist phenylephrine. Production of such an alpha 1-response reduced the size of a subsequently elicited quisqualate response. However production of transient [Ca2+]i spikes with caffeine did not alter the size of the quisqualate-induced spike. We conclude that hippocampal neurons possess two different types of quisqualate receptors. The first mediates quisqualate-induced depolarization and the second mediates Ca2+ mobilization from intracellular stores.
Mol Pharmacol 1989 May
PMID:Two distinct quisqualate receptors regulate Ca2+ homeostasis in hippocampal neurons in vitro. 256 4

Recent studies correlating the calcium current with, respectively, the clamp-imposed voltage and the calcium current in intact isolated mammalian cardiac myocytes are reviewed. The major findings are the following: With the exception of one group, all investigators agree that a calcium transient is never observed in the absence of a calcium current. In addition, there is a good correlation between voltage dependence of the calcium current and that of the calcium transient, although this correlation may vary among the cardiac tissues from different animal species. Repolarization clamp pulses from highly positive potentials produce a 'tail current' which is associated with a 'tail calcium transient'. The calcium transient is inhibited when the calcium current is blocked by calcium deprivation or substitution, or by the addition of calcium current antagonists, despite the fact that sarcoplasmic reticulum still contains calcium that can be released by caffeine (with inhibition of this release by ryanodine). These three findings are strongly in favor of a calcium-induced release of calcium and against the hypothesis of charge-movement-coupled release of calcium from the sarcoplasmic reticulum. The only finding that would be more in favor of the latter hypothesis (although still reconciliable with the former) is that repolarization occurring before the rapid rise of calcium transient is complete curtails the calcium transient. Thus, the possibility that charge movement might somehow regulate calcium-induced release of calcium cannot be excluded.
Mol Cell Biochem 1989 Sep 07
PMID:Appraisal of the physiological relevance of two hypothesis for the mechanism of calcium release from the mammalian cardiac sarcoplasmic reticulum: calcium-induced release versus charge-coupled release. 268 7

Doxorubicin, an anthracycline glycoside antibiotic which has been widely used for treatment of several types of cancer (Goormaghtigh and Ruysschaer, 1984), displays a clinically important cardiac toxicity (Young et al., 1981) that can be dissociated from the antitumor activity. Although the main sites of toxicity have been postulated to be on the muscle membranes (Goormaghtigh and Ruysschaer, 1984; Harris and Doroshow, 1985), no information is available for a direct doxorubicin effect on the Ca2+ fluxes in cardiac sarcoplasmic reticulum (SR). Previous studies have shown that micromolar doxorubicin triggers Ca2+ release from skeletal SR vesicles (Zorzato et al., 1985). The objective of this study was to examine the effect of doxorubicin or caffeine on Ca2+ fluxes in cardiac SR in the presence of various Ca2+ release inhibitors. Addition of either doxorubicin (C1/2 = 5 microM), or caffeine (C1/2 = 0.8 mM) triggered Ca2+ release from canine cardiac SR loaded with 45Ca2+ in the presence of 2 mM ATP. The maximal amount of Ca2+ release triggered by doxorubicin (38% of the total loaded Ca2+) was significantly higher than that released by caffeine (25%). Plots of the amount of Ca2+ release triggered by 20 microM doxorubicin or 2 mM caffeine vs. free Ca2+ concentration were a bell-shaped, with maximal Ca2+ release at 0.2 microM Ca2+. Ca2+ release triggered by either 20 microM doxorubicin or 2 mM caffeine was inhibited by ruthenium red (0.1 to 2 microM), ryanodine (1 to 100 microM) or tetracaine (0.1 to 1 mM), whereas 2 mM caffeine did not further activate Ca2+ release triggered by 50 microM doxorubicin, suggesting that the drugs may share the same Ca2+ release channel.
J Mol Cell Cardiol 1989 May
PMID:Doxorubicin-induced calcium release from cardiac sarcoplasmic reticulum vesicles. 277 2

Activation of alpha 1-adrenergic receptors in BC3H-1 muscle cells results in the rapid elevation of intracellular Ca2+, accompanied by an unusually slow and small increase in inositol 1,4,5-trisphosphate (IP3) formation [J. Biol. Chem. 263: 1952-1959 (1988); Mol. Pharmacol. 32: 376-383 (1987)]. To further assess the role of IP3 in receptor-stimulated Ca2+ mobilization, we have examined Ca2+ disposition in saponin-permeabilized BC3H-1 cells. Permeabilized cells loaded with tracer 45Ca2+ in a buffer containing 100 nM free Ca2+ accumulated greater than 75% of their Ca2+ into an ATP-sensitive compartment and were insensitive to inhibitors of mitochondrial Ca2+ uptake. Application of IP3 resulted in a rapid increase in 45Ca2+ efflux. Under isotopic equilibrium, approximately 90% of the total membrane-enclosed 45Ca2+ was released by 10 microM IP3 within 30 sec. Maximally and half-maximally effective concentrations of IP3 were 22 microM and 0.9 microM, respectively. Application of 10 microM GTP, but not guanine triphosphate-gamma-sulfate, resulted in a slight increase in 45Ca2+ efflux, which reflected a loss in total cellular Ca2+. The GTP-mediated response was slower and of far smaller magnitude than that mediated by IP3. A Ca2+-triggered Ca2+ release mechanism appears not to amplify the receptor response in BC3H-1 cells, inasmuch as 45Ca2+ efflux was not appreciably increased by elevated concentrations of free Ca2+. Furthermore, caffeine and ryanodine had no effect on basal, IP3-mediated, or alpha 1-adrenergic-stimulated Ca2+ release from intact or permeabilized cells. In conclusion, BC3H-1 cells, although showing small and slow increases in IP3 formation upon agonist stimulation, exhibit normal sensitivity to IP3-elicited release of Ca2+ and low sensitivity to other candidate Ca2+-mobilizing agents. The IP3-sensitive Ca2+ stores may be localized within specialized compartments and may play a greater role in the maintenance of elevated cytosolic Ca2+ than in the initial response to receptor activation.
Mol Pharmacol 1989 Mar
PMID:Release of nonmitochondrial sequestered Ca2+ from permeabilized muscle cells in culture. 278 36

Methylxanthines, such as caffeine and theophylline, are adenosine receptor antagonists that exert dramatic effects upon the behavior of vertebrate animals by increasing attentiveness, anxiety, and convulsive activity. Benzodiazepines, such as flunitrazepam, generally exert behavioral effects that are opposite to those of methylxanthines. We report the finding that chronic exposure of embryonic brain neurons to caffeine or theophylline reduces the ability of gamma-aminobutyric acid (GABA) to potentiate the binding of [3H]flunitrazepam to the GABA/benzodiazepine receptor. This theophylline-induced "uncoupling" of GABA- and benzodiazepine-binding site allosteric interactions is blocked by chloroadenosine, an adenosine receptor agonist, indicating that the chronic effects of theophylline are mediated by a site that resembles an adenosine receptor. We speculate that adverse central nervous system effects of long-term exposure to methylxanthines such as in caffeine-containing beverages or theophylline-containing medications may be exerted by a cell-mediated modification of the GABAA receptor.
Mol Pharmacol 1988 May
PMID:Chronic caffeine or theophylline exposure reduces gamma-aminobutyric acid/benzodiazepine receptor site interactions. 283 48


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