scholarly journals Calcium signaling via two-pore channels: local or global, that is the question

2010 ◽  
Vol 298 (3) ◽  
pp. C430-C441 ◽  
Author(s):  
Michael X. Zhu ◽  
Jianjie Ma ◽  
John Parrington ◽  
Peter J. Calcraft ◽  
Antony Galione ◽  
...  
Keyword(s):  
Calcium Signaling ◽  
Calcium Release ◽  
Ryanodine Receptors ◽  
Calcium Stores ◽  
Calcium Signals ◽  
Calcium Release Channels ◽  
Intracellular Calcium Signaling ◽  
Global Signal ◽  
Rna Knockdown ◽  
Calcium Induced Calcium Release

Recently, we identified, for the first time, two-pore channels (TPCs, TPCN for gene name) as a novel family of nicotinic acid adenine dinucleotide phosphate (NAADP)-gated, endolysosome-targeted calcium release channels. Significantly, three subtypes of TPCs have been characterized, TPC1-3, with each being targeted to discrete acidic calcium stores, namely lysosomes (TPC2) and endosomes (TPC1 and TPC3). That TPCs act as NAADP-gated calcium release channels is clear, given that NAADP binds to high- and low-affinity sites associated with TPC2 and thereby induces calcium release and homologous desensitization, as observed in the case of endogenous NAADP receptors. Moreover, NAADP-evoked calcium signals via TPC2 are ablated by short hairpin RNA knockdown of TPC2 and by depletion of acidic calcium stores with bafilomycin. Importantly, however, NAADP-evoked calcium signals were biphasic in nature, with an initial phase of calcium release from lysosomes via TPC2, being subsequently amplified by calcium-induced calcium release (CICR) from the endoplasmic reticulum (ER). In marked contrast, calcium release via endosome-targeted TPC1 induced only spatially restricted calcium signals that were not amplified by CICR from the ER. These findings provide new insights into the mechanisms that cells may utilize to “filter” calcium signals via junctional complexes to determine whether a given signal remains local or is converted into a propagating global signal. Essentially, endosomes and lysosomes represent vesicular calcium stores, quite unlike the ER network, and TPCs do not themselves support CICR or, therefore, propagating regenerative calcium waves. Thus “quantal” vesicular calcium release via TPCs must subsequently recruit inositol 1,4,5-trisphoshpate receptors and/or ryanodine receptors on the ER by CICR to evoke a propagating calcium wave. This may call for a revision of current views on the mechanisms of intracellular calcium signaling. The purpose of this review is, therefore, to provide an appropriate framework for future studies in this area.

The geometry of the EJSR Z-rete in avian cardiac muscle

1995 ◽  
Vol 53 ◽  
pp. 940-941
Author(s):  
J.R. Sommer ◽  
T. High ◽  
I. Taylor
Keyword(s):  
Cardiac Muscle ◽  
Muscle Activation ◽  
Calcium Release ◽  
Ryanodine Receptors ◽  
Alternative Mechanism ◽  
Calcium Release Channels ◽  
Graded Response ◽  
Calcium Induced Calcium Release ◽  
Theoretical Considerations ◽  
Recent Demonstration

The junctional SRs (JSR) in skeletal and cardiac muscle in general, including extended junctional SR (EJSR) in avian hearts, are morphologic and functional homologies as shown by biochemical and morphometric evidence, including the recent demonstration that EJSR contains ryanodine receptors and binds [3H]-Ryanodine. Bird hearts have two aberrant membrane features: 1. absence of transverse tu-bules (TT) and, 2. extension of JSRs (thus: E-JSR) from peripheral couplings into the interior of the myocytes forming EJSR Z-retes that both surround and pervade Z-discs. Absence of TT calls for an alternative mechanism for global muscle activation in bird hearts for which EJSR may provide the anatomical substratum, a possibility supported by both experimental evidence, and recent theoretical considerations. Propagated calcium-induced calcium release (CICR) has been difficult to reconcile with the graded response of cardiac muscle to stimulation.2,cf.5 Propagation of an action potential along the Z-retes can be excluded. In the absence of TT, saltatory CICR as an alternative to propagated cardiac activation, is made plausible by the existence of EJSR which, (a) is demonstrably calcium-sensitive, (b) is well within < than 0.5μm of the regulatory proteins of cardiac myocytes and, (c) carries rows of proven, vicinal calcium release channels.

scholarly journals Calcium-Induced Calcium Release in Smooth Muscle

2000 ◽  
Vol 115 (5) ◽  
pp. 653-662 ◽  
Author(s):  
M.L. Collier ◽  
G. Ji ◽  
Y.-X. Wang ◽  
M.I. Kotlikoff
Keyword(s):  
Smooth Muscle ◽  
Calcium Release ◽  
Striated Muscle ◽  
Single Channel ◽  
Ryanodine Receptors ◽  
Cytosolic Calcium ◽  
Heart Cells ◽  
Tight Coupling ◽  
Calcium Induced Calcium Release ◽  
Ca2 Channels

Calcium-induced calcium release (CICR) has been observed in cardiac myocytes as elementary calcium release events (calcium sparks) associated with the opening of L-type Ca2+ channels. In heart cells, a tight coupling between the gating of single L-type Ca2+ channels and ryanodine receptors (RYRs) underlies calcium release. Here we demonstrate that L-type Ca2+ channels activate RYRs to produce CICR in smooth muscle cells in the form of Ca2+ sparks and propagated Ca2+ waves. However, unlike CICR in cardiac muscle, RYR channel opening is not tightly linked to the gating of L-type Ca2+ channels. L-type Ca2+ channels can open without triggering Ca2+ sparks and triggered Ca2+ sparks are often observed after channel closure. CICR is a function of the net flux of Ca2+ ions into the cytosol, rather than the single channel amplitude of L-type Ca2+ channels. Moreover, unlike CICR in striated muscle, calcium release is completely eliminated by cytosolic calcium buffering. Thus, L-type Ca2+ channels are loosely coupled to RYR through an increase in global [Ca2+] due to an increase in the effective distance between L-type Ca2+ channels and RYR, resulting in an uncoupling of the obligate relationship that exists in striated muscle between the action potential and calcium release.

scholarly journals Phosphorylation-Dependent Regulation of Ryanodine Receptors

2001 ◽  
Vol 153 (4) ◽  
pp. 699-708 ◽  
Author(s):  
Steven O. Marx ◽  
Steven Reiken ◽  
Yuji Hisamatsu ◽  
Marta Gaburjakova ◽  
Jana Gaburjakova ◽  
...  
Keyword(s):  
Ion Channels ◽  
Ion Channel ◽  
Calcium Release ◽  
Ryanodine Receptors ◽  
Rapid Identification ◽  
Calcium Release Channels ◽  
Macromolecular Complexes ◽  
Protein Binding Sites ◽  
Skeletal Muscle Contraction

Ryanodine receptors (RyRs), intracellular calcium release channels required for cardiac and skeletal muscle contraction, are macromolecular complexes that include kinases and phosphatases. Phosphorylation/dephosphorylation plays a key role in regulating the function of many ion channels, including RyRs. However, the mechanism by which kinases and phosphatases are targeted to ion channels is not well understood. We have identified a novel mechanism involved in the formation of ion channel macromolecular complexes: kinase and phosphatase targeting proteins binding to ion channels via leucine/isoleucine zipper (LZ) motifs. Activation of kinases and phosphatases bound to RyR2 via LZs regulates phosphorylation of the channel, and disruption of kinase binding via LZ motifs prevents phosphorylation of RyR2. Elucidation of this new role for LZs in ion channel macromolecular complexes now permits: (a) rapid mapping of kinase and phosphatase targeting protein binding sites on ion channels; (b) predicting which kinases and phosphatases are likely to regulate a given ion channel; (c) rapid identification of novel kinase and phosphatase targeting proteins; and (d) tools for dissecting the role of kinases and phosphatases as modulators of ion channel function.

Sarcoplasmic Reticulum Calcium Release Channels in Ventricles of Older Adult Hamsters

2006 ◽  
Vol 25 (1) ◽  
pp. 107-113 ◽  
Author(s):  
Peter A. Nicholl ◽  
Susan E. Howlett
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Older Adult ◽  
Binding Sites ◽  
Calcium Release ◽  
Ryanodine Receptors ◽  
Calcium Release Channels ◽  
Site Density ◽  
Age Related ◽  
Sarcoplasmic Reticulum Calcium ◽  
Age Related Changes

ABSTRACTWhether the density of sarcoplasmic reticulum (SR) calcium release channels / ryanodine receptors in the heart declines with age is not clear. We investigated age-related changes in the density of «3H»-ryanodine receptors in crude ventricular homogenates, which contained all ligand binding sites in heart and in isolated junctional SR membranes. Experiments utilized young (120 days) and older adult (300 days) hamsters. «3H»-ryanodine binding site density did not change with age in crude homogenate preparations, although total heart protein concentration increased significantly with age. In contrast, the density of «3H»-ryanodine binding sites decreased markedly in heavy SR membranes purified from older hearts. These results show that demonstration of age-related changes in cardiac ryanodine receptor density depends upon the preparation used. Furthermore, the increase in total ventricular protein with age suggests that normalization of data by membrane protein should be used with caution in studies of aging heart.

scholarly journals Essential requirement for two-pore channel 1 in NAADP-mediated calcium signaling

2009 ◽  
Vol 186 (2) ◽  
pp. 201-209 ◽  
Author(s):  
Eugen Brailoiu ◽  
Dev Churamani ◽  
Xinjiang Cai ◽  
Michael G. Schrlau ◽  
G. Cristina Brailoiu ◽  
...  
Keyword(s):  
Calcium Channels ◽  
Nicotinic Acid ◽  
Calcium Signaling ◽  
Calcium Release ◽  
Pore Channel ◽  
Pore Region ◽  
Calcium Signals ◽  
Essential Requirement ◽  
Molecular Identity ◽  
Conserved Residue

Nicotinic acid adenine dinucleotide phosphate (NAADP) is a widespread and potent calcium-mobilizing messenger that is highly unusual in activating calcium channels located on acidic stores. However, the molecular identity of the target protein is unclear. In this study, we show that the previously uncharacterized human two-pore channels (TPC1 and TPC2) are endolysosomal proteins, that NAADP-mediated calcium signals are enhanced by overexpression of TPC1 and attenuated after knockdown of TPC1, and that mutation of a single highly conserved residue within a putative pore region abrogated calcium release by NAADP. Thus, TPC1 is critical for NAADP action and is likely the long sought after target channel for NAADP.

scholarly journals Multiple Modes of Calcium-Induced Calcium Release in Sympathetic Neurons I

2001 ◽  
Vol 118 (1) ◽  
pp. 83-100 ◽  
Author(s):  
Meredith A. Albrecht ◽  
Stephen L. Colegrove ◽  
Jarin Hongpaisan ◽  
Natalia B. Pivovarova ◽  
S. Brian Andrews ◽  
...  
Keyword(s):  
Calcium Release ◽  
Sympathetic Neurons ◽  
Ryanodine Receptors ◽  
Flux Analysis ◽  
X Ray ◽  
Simultaneous Measurements ◽  
Weak Stimulation ◽  
Quantitative Properties ◽  
Calcium Induced Calcium Release ◽  
Uptake And Release

Many cells express ryanodine receptors (RyRs) whose activation is thought to amplify depolarization-evoked elevations in cytoplasmic Ca2+ concentration ([Ca2+]i) through a process of Ca2+-induced Ca2+ release (CICR). In neurons, it is usually assumed that CICR triggers net Ca2+ release from an ER Ca2+ store. However, since net ER Ca2+ transport depends on the relative rates of Ca2+ uptake and release via distinct pathways, weak activation of a CICR pathway during periods of ER Ca accumulation would have a totally different effect: attenuation of Ca2+ accumulation. Stronger CICR activation at higher [Ca2+]i could further attenuate Ca2+ accumulation or trigger net Ca2+ release, depending on the quantitative properties of the underlying Ca2+ transporters. This and the companion study (Hongpaisan, J., N.B. Pivovarova, S.L. Colgrove, R.D. Leapman, and D.D. Friel, and S.B. Andrews. 2001. J. Gen. Physiol. 118:101–112) investigate which of these CICR “modes” operate during depolarization-induced Ca2+ entry in sympathetic neurons. The present study focuses on small [Ca2+]i elevations (less than ∼350 nM) evoked by weak depolarization. The following two approaches were used: (1) Ca2+ fluxes were estimated from simultaneous measurements of [Ca2+]i and ICa in fura-2–loaded cells (perforated patch conditions), and (2) total ER Ca concentrations ([Ca]ER) were measured using X-ray microanalysis. Flux analysis revealed triggered net Ca2+ release during depolarization in the presence but not the absence of caffeine, and [Ca2+]i responses were accelerated by SERCA inhibitors, implicating ER Ca2+ accumulation, which was confirmed by direct [Ca]ER measurements. Ryanodine abolished caffeine-induced CICR and enhanced depolarization-induced ER Ca2+ accumulation, indicating that activation of the CICR pathway normally attenuates ER Ca2+ accumulation, which is a novel mechanism for accelerating evoked [Ca2+]i responses. Theory shows how such a low gain mode of CICR can operate during weak stimulation and switch to net Ca2+ release at high [Ca2+]i, a transition demonstrated in the companion study. These results emphasize the importance of the relative rates of Ca2+ uptake and release in defining ER contributions to depolarization-induced Ca2+ signals.

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.

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