A novel Ca2+-induced Ca2+ release mechanism mediated by neither inositol trisphosphate nor ryanodine receptors

2002 ◽  
Vol 361 (3) ◽  
pp. 605-611 ◽  
Author(s):  
Frank WISSING ◽  
Edmund P. NEROU ◽  
Colin W. TAYLOR
Keyword(s):  
Ryanodine Receptors ◽  
Ruthenium Red ◽  
Release Mechanism ◽  
Temperature Sensitive ◽  
Half Time ◽  
Ip3 Receptors ◽  
Inositol 1,4,5 Trisphosphate ◽  
Before And After ◽  
Partial Inactivation ◽  
Ca2 Channels

Members of both major families of intracellular Ca2+ channels, ryanodine and inositol 1,4,5-trisphosphate (IP3) receptors, are stimulated by substantial increases in cytosolic free Ca2+ concentration ([Ca2+]c). They thereby mediate Ca2+-induced Ca2+ release (CICR), which allows amplification and regenerative propagation of intracellular Ca2+ signals. In permeabilized hepatocytes, increasing [Ca2+]c to 10μM stimulated release of 30±1% of the intracellular stores within 60s; the EC50 occurred with a free [Ca2+] of 170±29nM. This CICR was abolished at 2°C. The same fraction of the stores was released by CICR before and after depletion of the IP3-sensitive stores, and CICR was not blocked by antagonists of IP3 receptors. Ryanodine, Ruthenium Red and tetracaine affected neither the Ca2+ content of the stores nor the CICR response. Sr2+ and Ba2+ (EC50 = 166nM and 28μM respectively) mimicked the effects of increased [Ca2+] on the intracellular stores, but Ni2+ blocked the passive leak of Ca2+ without blocking CICR. In rapid superfusion experiments, maximal concentrations of IP3 or Ca2+ stimulated Ca2+ release within 80ms. The response to IP3 was complete within 2s, but CICR continued for tens of seconds despite a slow [half-time (t1/2) = 3.54±0.07s] partial inactivation. CICR reversed rapidly (t1/2 = 529±17ms) and completely when the [Ca2+] was reduced. We conclude that hepatocytes express a novel temperature-sensitive, ATP-independent CICR mechanism that is reversibly activated by modest increases in [Ca2+], and does not require IP3 or ryanodine receptors or reversal of the sarcoplasmic/endoplasmic-reticulum Ca2+-ATPase. This mechanism may both regulate the Ca2+ content of the intracellular stores of unstimulated cells and allow even small intracellular Ca2+ signals to be amplified by CICR.

scholarly journals NAADP mobilizes Ca2+ from a thapsigargin-sensitive store in the nuclear envelope by activating ryanodine receptors

2003 ◽  
Vol 163 (2) ◽  
pp. 271-282 ◽  
Author(s):  
Julia V. Gerasimenko ◽  
Yoshio Maruyama ◽  
Kojiro Yano ◽  
Nick J. Dolman ◽  
Alexei V. Tepikin ◽  
...  
Keyword(s):  
Nuclear Envelope ◽  
Ryanodine Receptors ◽  
Ruthenium Red ◽  
Receptor Blockade ◽  
Ip3 Receptors ◽  
Ip3 Receptor ◽  
Transient Rise ◽  
Cyclic Adp Ribose ◽  
Inositol 1,4,5 Trisphosphate ◽  
Acidic Organelles

Ca2+ release from the envelope of isolated pancreatic acinar nuclei could be activated by nicotinic acid adenine dinucleotide phosphate (NAADP) as well as by inositol 1,4,5-trisphosphate (IP3) and cyclic ADP-ribose (cADPR). Each of these agents reduced the Ca2+ concentration inside the nuclear envelope, and this was associated with a transient rise in the nucleoplasmic Ca2+ concentration. NAADP released Ca2+ from the same thapsigargin-sensitive pool as IP3. The NAADP action was specific because, for example, nicotineamide adenine dinucleotide phosphate was ineffective. The Ca2+ release was unaffected by procedures interfering with acidic organelles (bafilomycin, brefeldin, and nigericin). Ryanodine blocked the Ca2+-releasing effects of NAADP, cADPR, and caffeine, but not IP3. Ruthenium red also blocked the NAADP-elicited Ca2+ release. IP3 receptor blockade did not inhibit the Ca2+ release elicited by NAADP or cADPR. The nuclear envelope contains ryanodine and IP3 receptors that can be activated separately and independently; the ryanodine receptors by either NAADP or cADPR, and the IP3 receptors by IP3.

The existence of inositol 1,4,5-trisphosphate and ryanodine receptors in mature bovine oocytes

Development ◽  
1995 ◽  
Vol 121 (8) ◽  
pp. 2645-2654 ◽  
Author(s):  
C. Yue ◽  
K.L. White ◽  
W.A. Reed ◽  
T.D. Bunch
Keyword(s):  
Ryanodine Receptors ◽  
Inhibitory Effect ◽  
Ruthenium Red ◽  
Calcium Oscillations ◽  
Ip3 Receptor ◽  
Cyclic Adp Ribose ◽  
Inositol 1,4,5 Trisphosphate ◽  
Bovine Oocytes ◽  
Continuous Injection

Intracellular Ca2+ (Ca2+i) transients during fertilization are critical to the activation of eggs in all species studied. Activation of both the inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) and ryanodine receptor (RYR) are responsible for the calcium oscillations during fertilization in sea urchin eggs. Using in vitro matured bovine oocytes loaded with Fura-2 AM ester as Ca2+i indicator, we addressed whether IP3Rs and RYRs coexist in mammalian eggs. Our results indicate that microinjection of 50–250 nM IP3 or 10–20 mM caffeine, 100–200 microM ryanodine and 4–8 microM cyclic ADP-ribose all induced Ca2+i release. The Ca2+i release induced by 250 nM IP3 could only be inhibited by prior injection of 1 mg/ml heparin which was overcome by continuous injection of IP3 to 1 microM. Prior injection of either 50 microM ruthenium red, 50 microM procaine or 1 % vehicle medium (VM) did not affect the Ca2+i release induced by IP3. Prior injection of heparin or VM did not affect the Ca2+i release induced by 10–20 mM caffeine or 200 microM ryanodine, but prior injection of 50 microM ruthenium red or procaine completely inhibited the effect of 10–20 mM caffeine. In addition, continuous injection of caffeine up to 40 mM overcame the inhibitory effect of ruthenium red or procaine. The same 50 microM concentration of ruthenium red or procaine only partially blocked the effect of 200 microM ryanodine, but 200 microM ruthenium red or procaine completely blocked the effect of 200 microM ryanodine.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Ca2+ release triggered by NAADP in hepatocyte microsomes

2006 ◽  
Vol 395 (2) ◽  
pp. 233-238 ◽  
Author(s):  
Miklós Mándi ◽  
Balázs Tóth ◽  
György Timár ◽  
Judit Bak
Keyword(s):  
Nicotinic Acid ◽  
Ryanodine Receptor ◽  
Sea Urchin ◽  
Mammalian Cells ◽  
Liver Microsomes ◽  
The Other ◽  
Release Mechanism ◽  
Ip3 Receptors ◽  
Rat Hepatocyte ◽  
Inositol 1,4,5 Trisphosphate

NAADP (nicotinic acid–adenine dinucleotide phosphate) is fast emerging as a new intracellular Ca2+-mobilizing messenger. NAADP induces Ca2+ release by a mechanism that is distinct from IP3 (inositol 1,4,5-trisphosphate)- and cADPR (cADP-ribose)-induced Ca2+ release. In the present study, we demonstrated that micromolar concentrations of NAADP trigger Ca2+ release from rat hepatocyte microsomes. Cross-desensitization to IP3 and cADPR by NAADP did not occur in liver microsomes. We report that non-activating concentrations of NAADP can fully inactivate the NAADP-sensitive Ca2+-release mechanism in hepatocyte microsomes. The ability of thapsigargin to block the NAADP-sensitive Ca2+ release is not observed in sea-urchin eggs or in intact mammalian cells. In contrast with the Ca2+ release induced by IP3 and cADPR, the Ca2+ release induced by NAADP was completely independent of the free extravesicular Ca2+ concentration and pH (in the range 6.4–7.8). The NAADP-elicited Ca2+ release cannot be blocked by the inhibitors of the IP3 receptors and the ryanodine receptor. On the other hand, verapamil and diltiazem do inhibit the NAADP- (but not IP3- or cADPR-) induced Ca2+ release.

Regulation of Ca2+-release-activated Ca2+ current (Icrac) by ryanodine receptors in inositol 1,4,5-trisphosphate-receptor-deficient DT40 cells

2001 ◽  
Vol 360 (1) ◽  
pp. 17-22 ◽  
Author(s):  
Kirill KISELYOV ◽  
Dong Min SHIN ◽  
Nikolay SHCHEYNIKOV ◽  
Tomohiro KUROSAKI ◽  
Shmuel MUALLEM
Keyword(s):  
Time Course ◽  
Ryanodine Receptors ◽  
Cell Types ◽  
Ruthenium Red ◽  
General Mechanism ◽  
Inward Rectification ◽  
Wild Type ◽  
Ip3 Receptor ◽  
Inositol 1,4,5 Trisphosphate ◽  
Dt40 Cells

Persistence of capacitative Ca2+ influx in inositol 1,4,5-trisphosphate (IP3) receptor (IP3R)-deficient DT40 cells (DT40IP3R-/−) raises the question of whether gating of Ca2+-release activated Ca2+ current (Icrac) by conformational coupling to Ca2+-release channels is a general mechanism of gating of these channels. In the present work we examined the properties and mechanism of activation of Icrac Ca2+ current in wild-type and DT40IP3R-/− cells. In both cell types passive depletion of internal Ca2+ stores by infusion of EGTA activated a Ca2+ current with similar characteristics and time course. The current was highly Ca2+-selective and showed strong inward rectification, all typical of Icrac. The activator of ryanodine receptor (RyR), cADP-ribose (cADPR), facilitated activation of Icrac, and the inhibitors of the RyRs, 8-N-cADPR, ryanodine and Ruthenium Red, all inhibited Icrac activation in DT40IP3R-/− cells, even after complete depletion of intracellular Ca2+ stores by ionomycin. Wild-type and DT40IP3R-/− cells express RyR isoforms 1 and 3. RyR levels were adapted in DT40IP3R-/− cells to a lower RyR3/RyR1 ratio than in wild-type cells. These results suggest that IP3Rs and RyRs can efficiently gate Icrac in DT40 cells and explain the persistence of Icrac gating by internal stores in the absence of IP3Rs.

Nitric oxide inhibits calcium release from sarcoplasmic reticulum of porcine tracheal smooth muscle cells

1997 ◽  
Vol 272 (1) ◽  
pp. L1-L7 ◽  
Author(s):  
M. S. Kannan ◽  
Y. S. Prakash ◽  
D. E. Johnson ◽  
G. C. Sieck
Keyword(s):  
Nitric Oxide ◽  
Smooth Muscle ◽  
Sarcoplasmic Reticulum ◽  
Calcium Release ◽  
Ryanodine Receptors ◽  
Tracheal Smooth Muscle ◽  
Nitric Oxide Donor ◽  
Ip3 Receptors ◽  
Video Fluorescence Microscopy ◽  
Inositol 1,4,5 Trisphosphate

In the present study, effects of the nitric oxide donor, S-nitroso-N-acetylpenicillamine (SNAP), on sarcoplasmic reticulum (SR) Ca2+ release were examined in freshly dissociated porcine tracheal smooth muscle (TSM) cells. Fura 2-loaded TSM cells were imaged using video fluorescence microscopy. SR Ca2+ release was induced by acetylcholine (ACh), which acts principally through inositol 1,4,5-trisphosphate (IP3) receptors, and by caffeine, which acts principally through ryanodine receptors (RyR). SNAP inhibited ACh-induced SR Ca2+ release at both 0 and 2.5 mM extracellular Ca2+. Degraded SNAP had no effect on ACh-induced SR Ca2+ release. SNAP also inhibited caffeine-induced SR Ca2+ release. ACh-induced Ca2+ influx was not affected by SNAP when SR reloading was blocked by thapsigargin. SNAP also did not affect SR Ca2+ reuptake. The membrane-permeant analogue of guanosine 3',5'-cyclic monophosphate (cGMP), 8-bromo-cGMP, mimicked the effects of SNAP. These results suggest that, in porcine TSM cells, SNAP reduces the intracellular Ca2+ response to ACh and caffeine by inhibiting SR Ca2+ release through both IP3 and RyR, but not by inhibiting influx or repletion of the SR Ca2+ stores. These effects are likely mediated via cGMP-dependent mechanisms.

scholarly journals Ca2+ entry into PC12 cells initiated by ryanodine receptors or inositol 1,4,5-trisphosphate receptors

1998 ◽  
Vol 329 (2) ◽  
pp. 349-357 ◽  
Author(s):  
L. Deborah BENNETT ◽  
D. Martin BOOTMAN ◽  
J. Michael BERRIDGE ◽  
R. Timothy CHEEK
Keyword(s):  
Endoplasmic Reticulum ◽  
Pc12 Cells ◽  
Ryanodine Receptors ◽  
Half Time ◽  
Free Medium ◽  
Excitable Cells ◽  
Inositol 1,4,5 Trisphosphate ◽  
Insp3 Receptors ◽  
Universal Mechanism ◽  
Stimulation Of

Capacitative Ca2+ entry (CCE) is a universal mechanism for refilling intracellular Ca2+ stores in electrically non-excitable cells. The situation in excitable cells is less clear, however, since they may rely on other entry mechanisms for Ca2+-store refilling. In the present study we investigated CCE in intact PC12 cells, using acetylcholine to bring about activation of InsP3 receptors (InsP3Rs), caffeine to activate ryanodine receptors (RyRs) and thapsigargin to inhibit sarco/endoplasmic reticulum Ca2+-ATPase pumps. We found that depletion of the InsP3-, caffeine- or thapsigargin-sensitive stores promoted Ca2+ entry, suggesting that stimulation of either InsP3Rs or RyRs can activate CCE. The CCE pathways activated by InsP3Rs, RyRs and thapsigargin appeared to be independent at least in part, since their effects were found to be additive. However, CCE triggered by caffeine, acetylcholine or thapsigargin progressively diminished with time. The decay of CCE caused by one agent also inhibited subsequent responses to the others, suggesting that some component of the CCE pathway is common to all intracellular Ca2+ stores. The magnitude of CCE stimulated by InsP3Rs or RyRs was related to the size of the stores; the InsP3-sensitive store was smaller than the RyR-sensitive store and triggered a smaller entry component. However, both stores filled with a similar half time (about 1 min), and both could be filled more rapidly by depolarization-induced Ca2+ entry through voltage-operated channels. A significant basal Ca2+ influx was apparent in PC12 cells. The basal entry component may be under the control of the InsP3-sensitive Ca2+ store, since short incubations in Ca2+-free medium depleted this store.

Agonist-activated, ryanodine-sensitive, IP3-insensitive Ca2+ release channels in longitudinal muscle of intestine

1994 ◽  
Vol 266 (5) ◽  
pp. C1421-C1431 ◽  
Author(s):  
J. F. Kuemmerle ◽  
K. S. Murthy ◽  
G. M. Makhlouf
Keyword(s):  
Longitudinal Muscle ◽  
Circular Muscle ◽  
Muscle Cells ◽  
Cell Types ◽  
Ruthenium Red ◽  
Effective Concentration ◽  
Channel Blockers ◽  
Inositol 1,4,5 Trisphosphate ◽  
Dissociation Constant Kd ◽  
Ca2 Channels

We have previously shown that Ca2+ mobilization in longitudinal muscle is not mediated by inositol 1,4,5-trisphosphate (IP3) and depends on an obligatory influx of Ca2+. The present study examined whether Ca2+ influx activates ryanodine-sensitive Ca2+ channels to cause Ca(2+)-induced Ca2+ release. Ryanodine bound with high affinity to longitudinal muscle cells [dissociation constant (Kd) 7.3 +/- 0.3 nM] and microsomes (Kd 7.5 +/- 0.4 nM) and induced concentration-dependent 45Ca2+ efflux [50% effective concentration (EC50) 1.3 +/- 0.5 nM], increase in cytosolic free Ca2+ (EC50 2.0 +/- 0.7 nM), and contraction (EC50 0.9 +/- 0.2 nM) but had no effect in circular muscle cells. Ryanodine binding and ryanodine-induced Ca2+ release were enhanced by caffeine and inhibited by dantrolene and ruthenium red but were not affected by IP3 or heparin. Changes in Ca2+ concentration (50-500 nM) caused Ca2+ release from permeabilized longitudinal but not circular muscle cells loaded with 45Ca2+. The contractile agonist cholecystokinin-8 elicited 45Ca2+ efflux in both circular and longitudinal muscle cells; efflux in longitudinal muscle cells was abolished by Ca2+ channel blockers and by pretreatment of the cells with ryanodine. Pretreatment with thapsigargin abolished agonist-induced 45Ca2+ efflux in both cell types. We conclude that ryanodine-sensitive IP3-insensitive Ca2+ release channels with properties similar to those in cardiac muscle are present in longitudinal but not circular muscle cells of intestine and that agonist-mediated Ca2+ influx activates these channels, leading to Ca(2+)-induced Ca2+ release.

NAADP, a new intracellular messenger that mobilizes Ca2+ from acidic stores

2006 ◽  
Vol 34 (5) ◽  
pp. 922-926 ◽  
Author(s):  
A. Galione
Keyword(s):  
Sea Urchin ◽  
Mammalian Cells ◽  
Ryanodine Receptors ◽  
Release Mechanism ◽  
Release Channel ◽  
Sea Urchin Egg ◽  
Wide Range ◽  
Inositol 1,4,5 Trisphosphate ◽  
Molecular Nature ◽  
Made In

NAADP (nicotinic acid–adenine dinucleotide phosphate) is a recently described Ca2+-mobilizing molecule. First characterized in the sea urchin egg, it has been shown to mobilize Ca2+ from intracellular stores in a wide range of cells from different organisms. It is a remarkably potent molecule, and recent reports show that its cellular levels change in response to a variety of agonists, confirming its role as a Ca2+-mobilizing messenger. In many cases, NAADP appears to interact with other Ca2+-mobilizing messengers such as IP3 (inositol 1,4,5-trisphosphate) and cADP-ribose in shaping cytosolic Ca2+ signals. What is not clear is the molecular nature of the NAADP-sensitive Ca2+ release mechanism and its subcellular localization. This review focuses on the recent progress made in sea urchin eggs, which indicates that NAADP activates a novel Ca2+ release channel distinct from the relatively well-characterized IP3 and ryanodine receptors. Furthermore, in the sea urchin egg, the NAADP-sensitive store appears to be separate from the endoplasmic reticulum and is most likely an acidic store. These findings have also been reinforced by similar findings in mammalian cells, and a unified model for NAADP-induced Ca2+ signalling is presented.

Refilling the inositol 1,4,5-trisphosphate-sensitive Ca2+ store in neuroblastoma x glioma hybrid NG108-15 cells

1993 ◽  
Vol 264 (3) ◽  
pp. C641-C653 ◽  
Author(s):  
T. M. Lo ◽  
S. A. Thayer
Keyword(s):  
Plasma Membrane ◽  
Inhibitory Concentration ◽  
Effective Concentration ◽  
Half Time ◽  
Dual Emission ◽  
Spectral Shifts ◽  
Inositol 1,4,5 Trisphosphate ◽  
The Status ◽  
Ca2 Channels

Bradykinin-induced increases in the intracellular free Ca2+ concentration ([Ca2+]i) were recorded in single NG108-15 cells with indo-1-based dual-emission microfluorimetry (50% effective concentration, 16 nM). A 1-min exposure to 30 nM bradykinin completely depleted the inositol 1,4,5-trisphosphate (IP3)-sensitive Ca2+ store; refilling the store required extracellular Ca2+ (half time, 2 min). Refilling the IP3-sensitive store was completely blocked by 1 microM La3+ and 10 microM nitrendipine, but not 10 microM verapamil, 10 microM flunarizine, 1 microM nitrendipine, or 0.1 microM La3+. Thapsigargin irreversibly depleted the Ca2+ store and prevented its refilling (half-maximal inhibitory concentration, 3 nM). Influx of Ca2+ across the plasma membrane did not increase after depletion of the IP3-sensitive store by exposure to bradykinin, although maintained presence of the agonist produced significant Ca2+ influx. Similarly, Mn2+ and Ba2+ influx, as measured by indo-1 quenching and spectral shifts, did not increase following depletion of IP3-sensitive store. In contrast to depletion of the IP3-sensitive Ca2+ store by bradykinin, thapsigargin (10 nM) treatment produced Ca2+ and Ba2+ influx. We conclude that after Ca2+ mobilization, the IP3-sensitive Ca2+ store in NG108-15 cells is refilled with cytoplasmic Ca2+ via a thapsigargin-sensitive Ca(2+)-Mg(2+)-ATPase. Cytoplasmic Ca2+ is replenished by a persistent leak of Ca2+ across the plasma membrane. This leak is not modulated by the status of the intracellular Ca2+ store. In NG108-15 cells, agonist and thapsigargin-evoked Ca2+ entry are mediated by activation of plasmalemmal Ca2+ channels independent of the status of the IP3-sensitive intracellular Ca2+ store.

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