scholarly journals Calcium Release Channels: Structure and Function of IP3 Receptors and Ryanodine Receptors

2021 ◽  
Author(s):  
Kellie A Woll ◽  
Filip Van Petegem
Keyword(s):  
Small Molecules ◽  
Calcium Release ◽  
Current Knowledge ◽  
Ryanodine Receptors ◽  
Ip3 Receptors ◽  
Electron Microscopic ◽  
Channel Opening ◽  
And Function ◽  
Opening And Closing ◽  
Common Architecture

Ca2+-release channels are giant membrane proteins that control the release of Ca2+ from the endoplasmic and sarcoplasmic reticulum. The two members, ryanodine receptors (RyRs) and inositol-1,4,5-trisphosphate Receptors (IP3Rs), are evolutionarily related and are both activated by cytosolic Ca2+. They share a common architecture, but RyRs have evolved additional modules in the cytosolic region. Their massive size allows for the regulation by tens of proteins and small molecules, which can affect the opening and closing of the channels. In addition to Ca2+, other major triggers include IP3 for the IP3Rs, and depolarization of the plasma membrane for a particular RyR subtype. Their size has made them popular targets for study via electron microscopic methods, with current structures culminating near 3Å. The available structures have provided many new mechanistic insights int the binding of auxiliary proteins and small molecules, how these can regulate channel opening, and the mechanisms of disease-associated mutations. They also help scrutinize previously proposed binding sites, as some of these are now incompatible with the structures. Many questions remain around the structural effects of post-translational modifications, additional binding partners, and the higher-order complexes these channels can make in situ. This review summarizes our current knowledge about the structures of Ca2+-release channels and how this informs on their function.

Modulation of type-1 Ins(1,4,5)P3 receptor channels by the FK506-binding protein, FKBP12

2002 ◽  
Vol 361 (2) ◽  
pp. 401-407 ◽  
Author(s):  
Sheila L. DARGAN ◽  
Edward J. A. LEA ◽  
Alan P. DAWSON
Keyword(s):  
Lipid Bilayers ◽  
Calcium Release ◽  
Single Channel ◽  
Binding Protein ◽  
Ryanodine Receptors ◽  
Fk506 Binding Protein ◽  
Single Channel Activity ◽  
And Function ◽  
First Time

FK506-binding protein (FKBP12) is highly expressed in neuronal tissue, where it is proposed to localize calcineurin to intracellular calcium-release channels, ryanodine receptors and Ins(1,4,5)P3 receptors (InsP3Rs). The effects of FKBP12 on ryanodine receptors have been well characterized but the nature and function of binding of FKBP12 to InsP3R is more controversial, with evidence for and against a tight interaction between these two proteins. To investigate this, we incorporated purified type-1 InsP3R from rat cerebellum into planar lipid bilayers to monitor the effects of exogenous recombinant FKBP12 on single-channel activity, using K+ as the current carrier. Here we report for the first time that FKBP12 causes a substantial change in single-channel properties of the type-1 InsP3R, specifically to increase the amount of time the channel spends in a fully open state. In the presence of ATP, FKBP12 can also induce co-ordinated gating with neighbouring receptors. The effects of FKBP12 were reversed by FK506. We also present data showing that rapamycin, at sub-optimal concentrations of Ins(2,4,5)P3, decreases the rate of calcium release from cerebellar microsomes. These results provide evidence for a direct functional interaction between FKBP12 and the type-1 InsP3R.

scholarly journals Clusters of calcium release channels harness the Ising phase transition to confine their elementary intracellular signals

2017 ◽  
Vol 114 (29) ◽  
pp. 7525-7530 ◽  
Author(s):  
Anna V. Maltsev ◽  
Victor A. Maltsev ◽  
Michael D. Stern
Keyword(s):  
Phase Transition ◽  
Statistical Physics ◽  
Calcium Release ◽  
Cell Function ◽  
Particle System ◽  
Signal To Noise Ratio ◽  
Ryanodine Receptors ◽  
High Amplitude ◽  
Ip3 Receptors ◽  
Cooperative Action

Intracellular Ca signals represent a universal mechanism of cell function. Messages carried by Ca are local, rapid, and powerful enough to be delivered over the thermal noise. A higher signal-to-noise ratio is achieved by a cooperative action of Ca release channels such as IP3 receptors or ryanodine receptors arranged in clusters (release units) containing a few to several hundred release channels. The channels synchronize their openings via Ca-induced Ca release, generating high-amplitude local Ca signals known as puffs in neurons and sparks in muscle cells. Despite the positive feedback nature of the activation, Ca signals are strictly confined in time and space by an unexplained termination mechanism. Here we show that the collective transition of release channels from an open to a closed state is identical to the phase transition associated with the reversal of magnetic field in an Ising ferromagnet. Our simple quantitative criterion closely predicts the Ca store depletion level required for spark termination for each cluster size. We further formulate exact requirements that a cluster of release channels should satisfy in any cell type for our mapping to the Ising model and the associated formula to remain valid. Thus, we describe deterministically the behavior of a system on a coarser scale (release unit) that is random on a finer scale (release channels), bridging the gap between scales. Our results provide exact mapping of a nanoscale biological signaling model to an interacting particle system in statistical physics, making the extensive mathematical apparatus available to quantitative biology.

scholarly journals Mini-dystrophin Expression Down-regulates IP3-mediated Calcium Release Events in Resting Dystrophin-deficient Muscle Cells

2006 ◽  
Vol 128 (2) ◽  
pp. 219-230 ◽  
Author(s):  
Haouaria Balghi ◽  
Stéphane Sebille ◽  
Ludivine Mondin ◽  
Anne Cantereau ◽  
Bruno Constantin ◽  
...  
Keyword(s):  
Calcium Signaling ◽  
Signaling Pathway ◽  
Intracellular Signaling ◽  
Calcium Release ◽  
Ryanodine Receptors ◽  
Release Site ◽  
Cell Types ◽  
Ip3 Receptors ◽  
Calcium Signaling Pathway ◽  
Gi Protein

We present here evidence for the enhancement, at rest, of an inositol 1,4,5-trisphosphate (IP3)–mediated calcium signaling pathway in myotubes from dystrophin-deficient cell lines (SolC1(−)) as compared to a cell line from the same origin but transfected with mini-dystrophin (SolD(+)). With confocal microscopy, the number of sites discharging calcium (release site density [RSD]) was quantified and found more elevated in SolC1(−) than in SolD(+) myotubes. Variations of membrane potential had no significant effect on this difference, and higher resting [Ca2+]i in SolC1(−) (Marchand, E., B. Constantin, H. Balghi, M.C. Claudepierre, A. Cantereau, C. Magaud, A. Mouzou, G. Raymond, S. Braun, and C. Cognard. 2004. Exp. Cell Res. 297:363–379) cannot explain alone higher RSD. The exposure with SR Ca2+ channel inhibitors (ryanodine and 2-APB) and phospholipase C inhibitor (U73122) significantly reduced RSD in both cell types but with a stronger effect in dystrophin-deficient SolC1(−) myotubes. Immunocytochemistry allowed us to localize ryanodine receptors (RyRs) as well as IP3 receptors (IP3Rs), IP3R-1 and IP3R-2 isoforms, indicating the presence of both RyRs-dependent and IP3-dependent release systems in both cells. We previously reported evidence for the enhancement, through a Gi protein, of the IP3-mediated calcium signaling pathway in SolC1(−) as compared to SolD(+) myotubes during a high K+ stimulation (Balghi, H., S. Sebille, B. Constantin, S. Patri, V. Thoreau, L. Mondin, E. Mok, A. Kitzis, G. Raymond, and C. Cognard. 2006. J. Gen. Physiol. 127:171–182). Here we show that, at rest, these regulation mechanisms are also involved in the modulation of calcium release activities. The enhancement of resting release activity may participate in the calcium overload observed in dystrophin-deficient myotubes, and our findings support the hypothesis of the regulatory role of mini-dystrophin on intracellular signaling.

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 Mini-dystrophin Expression Down-regulates Overactivation of G Protein–mediated IP3 Signaling Pathway in Dystrophin-deficient Muscle Cells

2006 ◽  
Vol 127 (2) ◽  
pp. 171-182 ◽  
Author(s):  
Haouaria Balghi ◽  
Stéphane Sebille ◽  
Bruno Constantin ◽  
Sylvie Patri ◽  
Vincent Thoreau ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Intracellular Signaling ◽  
Calcium Release ◽  
Ryanodine Receptors ◽  
Inhibitory Effect ◽  
Ip3 Receptors ◽  
High Potassium ◽  
Gi Protein ◽  
Kinetics Of ◽  
Sr Calcium Release

We present here evidence for the enhancement of an inositol 1,4,5-trisphosphate (IP3) mediated calcium signaling pathway in myotubes from dystrophin-deficient cell lines (SolC1(−)) as compared to a cell line from the same origin but transfected with mini-dystrophin (SolD(+)). With confocal microscopy, we demonstrated that calcium rise, induced by the perifusion of a solution containing a high potassium concentration, was higher in SolC1(−) than in SolD(+) myotubes. The analysis of amplitude and kinetics of the calcium increase in SolC1(−) and in SolD(+) myotubes during the exposure with SR Ca2+ channel inhibitors (ryanodine and 2-APB) suggested the presence of two mechanisms of SR calcium release: (1) a fast SR calcium release that depended on ryanodine receptors and (2) a slow SR calcium release mediated by IP3 receptors. Detection analyses of mRNAs (reverse transcriptase [RT]-PCR) and proteins (Western blot and immunolocalization) demonstrated the presence of the three known isoforms of IP3 receptors in both SolC1(−) and SolD(+) myotubes. Furthermore, analysis of the kinetics of the rise in calcium revealed that the slow IP3-dependent release may be increased in the SolC1(−) as compared to the SolD(+), suggesting an inhibitory effect of mini-dystrophin in this signaling pathway. Upon incubation with pertussis toxin (PTX), an inhibitory effect similar to that of the IP3R inhibitor (2-APB) was observed on K+-evoked calcium release. This result suggests the involvement of a Gi protein upstream of the IP3 pathway in these stimulation conditions. A hypothetical model is depicted in which both Gi protein and IP3 production could be involved in K+-evoked calcium release as well as a possible interaction with mini-dystrophin. Our findings demonstrate the existence of a potential relationship between mini-dystrophin and SR calcium release as well as a regulatory role of mini-dystrophin on intracellular signaling.

scholarly journals Ryanodine Receptors: Structure, Expression, Molecular Details, and Function in Calcium Release

2010 ◽  
Vol 2 (11) ◽  
pp. a003996-a003996 ◽  
Author(s):  
J. T. Lanner ◽  
D. K. Georgiou ◽  
A. D. Joshi ◽  
S. L. Hamilton
Keyword(s):  
Calcium Release ◽  
Ryanodine Receptors ◽  
And Function

Expression and functional characterization of SCaMPER: a sphingolipid-modulated calcium channel of cardiomyocytes

2003 ◽  
Vol 284 (3) ◽  
pp. C780-C790 ◽  
Author(s):  
Amy L. Cavalli ◽  
Nicole W. O'Brien ◽  
Steven B. Barlow ◽  
Romeo Betto ◽  
Christopher C. Glembotski ◽  
...  
Keyword(s):  
Calcium Channel ◽  
Calcium Release ◽  
Cardiac Tissue ◽  
Ryanodine Receptors ◽  
Functional Characterization ◽  
Substantial Reduction ◽  
Pcr Cloning ◽  
Cellular Events ◽  
T Tubules ◽  
And Function

Calcium channels are important in a variety of cellular events including muscle contraction, signaling, proliferation, and apoptosis. Sphingolipids have been recognized as mediators of intracellular calcium release through their actions on a calcium channel, sphingolipid calcium release-mediating protein of the endoplasmic reticulum (SCaMPER). The current study investigates the expression and function of SCaMPER in cardiomyocytes. Northern analyses and RT-PCR cloning and sequencing revealed SCaMPER expression in both human and rat cardiac tissue. Immunofluorescence and Western blot analyses demonstrated that SCaMPER is abundant in cardiac tissue and is localized to the sarcotubular junction. This was confirmed by the colocalization of SCaMPER with dihydropyridine and ryanodine receptors by confocal microscopy. Purified T tubules were shown to contain SCaMPER and immunoelectron micrographs suggested that SCaMPER is located to the junctional T tubules, but a junctional SR localization cannot be ruled out. The sphingolipid ligand for SCaMPER, sphingosylphosphorylcholine (SPC), initiated calcium release from the cardiomyocyte SR. Importantly, antisense knockdown of SCaMPER mRNA produced a substantial reduction of sphingolipid-induced calcium release, suggesting that SCaMPER is a potentially important calcium channel of cardiomyocytes.

Metabotropic glutamate receptor-mediated cyclic ADP ribose signalling

2015 ◽  
Vol 43 (3) ◽  
pp. 405-409 ◽  
Author(s):  
Aidan Kaar ◽  
Mark G. Rae
Keyword(s):  
Metabotropic Glutamate Receptors ◽  
Calcium Release ◽  
Metabotropic Glutamate Receptor ◽  
Ryanodine Receptors ◽  
Calcium Stores ◽  
Ip3 Receptors ◽  
Metabotropic Glutamate ◽  
Group I ◽  
Cyclic Adp Ribose ◽  
Key Aspects

Group I metabotropic glutamate receptors (I-mGluRs) modulate numerous cellular functions such as specific membrane currents and neurotransmitter release linked to their ability to mobilize calcium from intracellular calcium stores. As such, most I-mGluR research to date has focused on the coupling of these receptors to phospholipase C (PLC)-dependent and inositol (1,4,5) trisphosphate (IP3)-mediated calcium release via activation of IP3 receptors located upon the sarco/endoplasmic reticulum. However, there are now numerous examples of PLC- and IP3-independent I-mGluR-evoked signals, which may instead be mediated by activation of ryanodine receptors (RyRs). A prime candidate for mediating this coupling between I-mGluR activation and RyR opening is cyclic ADP ribose (cADPR) and, indeed, several of these PLC-/IP3-independent I-mGluR-evoked calcium signals have now been shown to be mediated wholly or partly by cADPR-evoked activation of RyRs. The contribution of cADPR signalling to I-mGluR-mediated responses is relatively complex, dependent as it is on factors such as cell type, excitation state of the cell and location of I-mGluRs on the cell. However, these factors notwithstanding, I-mGluR-mediated cADPR signalling remains poorly characterized, with several key aspects yet to be fully elucidated such as (1) the range of stimuli which evoke cADPR production, (2) the specific molecular mechanism(s) coupling cADPR to RyR activation and (3) the contribution of cADPR-mediated responses to downstream outputs such as synaptic plasticity. Furthermore, it is possible that the cADPR pathway may play a role in diseases underpinned by dysregulated calcium homoeostasis such as Alzheimer's disease (AD).

Structure and function of the neuronal endomembrane system

1993 ◽  
Vol 51 ◽  
pp. 98-99
Author(s):  
Maryann E. Martone ◽  
Victoria M. Simpliciano ◽  
Ying Zhang ◽  
Thomas J. Deerinck ◽  
Mark H. Ellisman
Keyword(s):  
Intracellular Calcium ◽  
Calcium Release ◽  
Smooth Endoplasmic Reticulum ◽  
Ryanodine Receptors ◽  
Cell Types ◽  
Calcium Stores ◽  
Endomembrane System ◽  
Ip3 Receptor ◽  
And Function ◽  
Cerebellar Purkinje Neurons

Components of the endomembrane system in a variety of cell types appear to function in the storage and release of calcium similar to the muscle sarcoplasmic reticulum. Many proteins involved in intracellular calcium regulation in skeletal or smooth muscle, e.g. Ca++ ATPase, calsequestrin, the inositol l,4,5,trisphosphate (TP3) receptor and the ryanodine binding protein, are found in the nervous system where they are particularly abundant within the smooth endoplasmic reticulum (SER) of cerebellar Purkinje neurons. Immunolocalization studies suggest, however, that calcium regulatory proteins are not uniformly distributed within the SER but are concentrated in or excluded from certain domains. For example, the IP3 and ryanodine receptors, two distinct calcium channels which mediate calcium release by different ligands, are found associated with the SER in cell bodies and dendrites of chick cerebellum but only the IP3 receptor is found within dendritic spines. These results are consistent with evidence that cells may possess multiple intracellular calcium stores that are pharmacologically, spatially and perhaps physically distinct.

scholarly journals On a Magical Mystery Tour with 8-Bromo-Cyclic ADP-Ribose: From All-or-None Block to Nanojunctions and the Cell-Wide Web

Molecules ◽  
2020 ◽  
Vol 25 (20) ◽  
pp. 4768
Author(s):  
A. Mark Evans
Keyword(s):  
Calcium Release ◽  
Calcium Influx ◽  
Ryanodine Receptors ◽  
Smooth Muscles ◽  
Calcium Flux ◽  
Ip3 Receptors ◽  
Pharmacological Profile ◽  
Cellular Functions ◽  
Calcium Signals ◽  
Influx Pathways

A plethora of cellular functions are controlled by calcium signals, that are greatly coordinated by calcium release from intracellular stores, the principal component of which is the sarco/endooplasmic reticulum (S/ER). In 1997 it was generally accepted that activation of various G protein-coupled receptors facilitated inositol-1,4,5-trisphosphate (IP3) production, activation of IP3 receptors and thus calcium release from S/ER. Adding to this, it was evident that S/ER resident ryanodine receptors (RyRs) could support two opposing cellular functions by delivering either highly localised calcium signals, such as calcium sparks, or by carrying propagating, global calcium waves. Coincidentally, it was reported that RyRs in mammalian cardiac myocytes might be regulated by a novel calcium mobilising messenger, cyclic adenosine diphosphate-ribose (cADPR), that had recently been discovered by HC Lee in sea urchin eggs. A reputedly selective and competitive cADPR antagonist, 8-bromo-cADPR, had been developed and was made available to us. We used 8-bromo-cADPR to further explore our observation that S/ER calcium release via RyRs could mediate two opposing functions, namely pulmonary artery dilation and constriction, in a manner seemingly independent of IP3Rs or calcium influx pathways. Importantly, the work of others had shown that, unlike skeletal and cardiac muscles, smooth muscles might express all three RyR subtypes. If this were the case in our experimental system and cADPR played a role, then 8-bromo-cADPR would surely block one of the opposing RyR-dependent functions identified, or the other, but certainly not both. The latter seemingly implausible scenario was confirmed. How could this be, do cells hold multiple, segregated SR stores that incorporate different RyR subtypes in receipt of spatially segregated signals carried by cADPR? The pharmacological profile of 8-bromo-cADPR action supported not only this, but also indicated that intracellular calcium signals were delivered across intracellular junctions formed by the S/ER. Not just one, at least two. This article retraces the steps along this journey, from the curious pharmacological profile of 8-bromo-cADPR to the discovery of the cell-wide web, a diverse network of cytoplasmic nanocourses demarcated by S/ER nanojunctions, which direct site-specific calcium flux and may thus coordinate the full panoply of cellular processes.

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