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 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.

scholarly journals The genie in the bottle-magnified calcium signaling in dorsolateral prefrontal cortex

2020 ◽  
Author(s):  
Amy F. T. Arnsten ◽  
Dibyadeep Datta ◽  
Min Wang
Keyword(s):  
Prefrontal Cortex ◽  
Calcium Channels ◽  
Calcium Signaling ◽  
Dorsolateral Prefrontal Cortex ◽  
Molecular Mechanisms ◽  
Calcium Release ◽  
Cognitive Disorders ◽  
Camp Signaling ◽  
Increased Risk ◽  
Dorsolateral Prefrontal

AbstractNeurons in the association cortices are particularly vulnerable in cognitive disorders such as schizophrenia and Alzheimer’s disease, while those in primary visual cortex remain relatively resilient. This review proposes that the special molecular mechanisms needed for higher cognitive operations confer vulnerability to dysfunction, atrophy, and neurodegeneration when regulation is lost due to genetic and/or environmental insults. Accumulating data suggest that higher cortical circuits rely on magnified levels of calcium (from NMDAR, calcium channels, and/or internal release from the smooth endoplasmic reticulum) near the postsynaptic density to promote the persistent firing needed to maintain, manipulate, and store information without “bottom-up” sensory stimulation. For example, dendritic spines in the primate dorsolateral prefrontal cortex (dlPFC) express the molecular machinery for feedforward, cAMP–PKA–calcium signaling. PKA can drive internal calcium release and promote calcium flow through NMDAR and calcium channels, while in turn, calcium activates adenylyl cyclases to produce more cAMP–PKA signaling. Excessive levels of cAMP–calcium signaling can have a number of detrimental effects: for example, opening nearby K+ channels to weaken synaptic efficacy and reduce neuronal firing, and over a longer timeframe, driving calcium overload of mitochondria to induce inflammation and dendritic atrophy. Thus, calcium–cAMP signaling must be tightly regulated, e.g., by agents that catabolize cAMP or inhibit its production (PDE4, mGluR3), and by proteins that bind calcium in the cytosol (calbindin). Many genetic or inflammatory insults early in life weaken the regulation of calcium–cAMP signaling and are associated with increased risk of schizophrenia (e.g., GRM3). Age-related loss of regulatory proteins which result in elevated calcium–cAMP signaling over a long lifespan can additionally drive tau phosphorylation, amyloid pathology, and neurodegeneration, especially when protective calcium binding proteins are lost from the cytosol. Thus, the “genie” we need for our remarkable cognitive abilities may make us vulnerable to cognitive disorders when we lose essential regulation.

scholarly journals Excess of glucocorticoid induces myocardial remodeling and alteration of calcium signaling in cardiomyocytes

2011 ◽  
Vol 209 (1) ◽  
pp. 105-114 ◽  
Author(s):  
Priyanka De ◽  
Sreerupa Ghose Roy ◽  
Dipak Kar ◽  
Arun Bandyopadhyay
Keyword(s):  
Calcium Channels ◽  
Calcium Signaling ◽  
Calcium Release ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Weight Ratio ◽  
Left Ventricular ◽  
Neonatal Rat ◽  
Heart Weight ◽  
Altered Expression

Ventricular dysfunction is one of the important side effects of the anti-inflammatory agent, glucocorticoid (GC). The present study was undertaken to examine whether abnormal calcium signaling is responsible for cardiac dysfunction due to an excess of GC hormone. The synthetic GC drug, dexamethasone (DEX), significantly (P<0.001, n=20) increased heart weight to body weight ratio, left ventricular remodeling, and fibrosis. The microarray analysis showed altered expression of several genes encoding calcium cycling/ion channel proteins in DEX-treated rat heart. The altered expression of some of the genes was validated by real-time PCR and western blotting analyses. The expression of the L-type calcium channels and calsequestrin was increased, whereas sarcoendoplasmic reticulum calcium transport ATPase 2a (SERCA2a) and junctin mRNAs were significantly reduced in DEX-treated rat left ventricular tissues. In neonatal rat ventricular cardiomyocytes, DEX also increased the level of mRNAs of atrial- and brain natriuretic peptides, L-type calcium channels, and calsequestrin after 24 h of treatment, which were mostly restored by mifepristone. The caffeine-induced calcium release was prolonged by DEX compared to the sharp release in control cardiomyocytes. Taken together, these data show that impaired calcium kinetics may be responsible for cardiac malfunction by DEX. The results are important in understanding the pathophysiology of the heart in patients treated with excess GC.

scholarly journals Simulation of calcium signaling in fine astrocytic processes: effect of spatial properties on spontaneous activity

2019 ◽  
Author(s):  
Denizot Audrey ◽  
Arizono Misa ◽  
Nägerl U. Valentin ◽  
Soula Hédi ◽  
Berry Hugues
Keyword(s):  
Calcium Channels ◽  
Calcium Signaling ◽  
Spatial Data ◽  
Spatial Organization ◽  
Spatial Scales ◽  
Cytosolic Calcium ◽  
Calcium Signals ◽  
Copy Numbers ◽  
The Central Nervous System ◽  
Transient Variations

AbstractAstrocytes, a glial cell type of the central nervous system, have emerged as detectors and regulators of neuronal information processing. Astrocyte excitability resides in transient variations of free cytosolic calcium concentration over a range of temporal and spatial scales, from sub-microdomains to waves propagating throughout the cell. Despite extensive experimental approaches, it is not clear how these signals are transmitted to and integrated within an astrocyte. The localization of the main molecular actors and the geometry of the system, including calcium channels IP3R spatial organization, are deemed essential. However, as most calcium signals occur in astrocytic ramifications that are too fine to be resolved by conventional light microscopy, most of those spatial data are unknown and computational modeling remains the only methodology to study this issue. Here, we propose an IP3R-mediated calcium signaling model for dynamics in such small sub-cellular volumes. To account for the expected stochasticity and low copy numbers, our model is both spatially explicit and particle-based. Extensive simulations show that spontaneous calcium signals arise in the model via the interplay between excitability and stochasticity. The model reproduces the main forms of calcium signals and indicates that their frequency crucially depends on the spatial organization of the IP3R channels. Importantly, we show that two processes expressing exactly the same calcium channels can display different types of calcium signals depending on channels spatial organization. Our model with realistic process volume and calcium concentrations successfully reproduces spontaneous calcium signals that we measured in calcium micro-domains with confocal microscopy. To our knowledge, this model is the first model suited to investigate calcium dynamics in fine astrocytic processes and to propose plausible mechanisms responsible for their variability.

scholarly journals The Impact of Vitamin D3Supplementation on Mechanisms of Cell Calcium Signaling in Chronic Kidney Disease

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Ingrid Lajdova ◽  
Viera Spustova ◽  
Adrian Oksa ◽  
Zuzana Kaderjakova ◽  
Dusan Chorvat ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Calcium Signaling ◽  
Calcium Homeostasis ◽  
Calcium Release ◽  
Calcium Entry ◽  
Regulatory Mechanisms ◽  
Cell Calcium ◽  
Crac Channels ◽  
The Impact

Intracellular calcium concentration in peripheral blood mononuclear cells (PBMCs) of patients with chronic kidney disease (CKD) is significantly increased, and the regulatory mechanisms maintaining cellular calcium homeostasis are impaired. The purpose of this study was to examine the effect of vitaminD3on predominant regulatory mechanisms of cell calcium homeostasis. The study involved 16 CKD stages 2-3 patients with vitamin D deficiency treated with cholecalciferol 7000–14000 IU/week for 6 months. The regulatory mechanisms of calcium signaling were studied in PBMCs and red blood cells. After vitaminD3supplementation, serum concentration of 25(OH)D3increased (P<0.001) and[Ca2+]idecreased (P<0.001). The differences in[Ca2+]iwere inversely related to differences in 25(OH)D3concentration (P<0.01). VitaminD3supplementation decreased the calcium entry through calcium release activated calcium (CRAC) channels and purinergic P2X7channels. The function of P2X7receptors was changed in comparison with their baseline status, and the expression of these receptors was reduced. There was no effect of vitaminD3on P2X7pores and activity of plasma membrane Ca2+-ATPases. VitaminD3supplementation had a beneficial effect on[Ca2+]idecreasing calcium entry via CRAC and P2X7channels and reducing P2X7receptors expression.

scholarly journals Modulation of calcium signaling depends on the oligosaccharide of GM1 in Neuro2a mouse neuroblastoma cells

2020 ◽  
Vol 37 (6) ◽  
pp. 713-727
Author(s):  
Giulia Lunghi ◽  
Maria Fazzari ◽  
Erika Di Biase ◽  
Laura Mauri ◽  
Sandro Sonnino ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Calcium Channels ◽  
Calcium Signaling ◽  
Intracellular Calcium ◽  
Calcium Imaging ◽  
Neuroblastoma Cells ◽  
Ganglioside Gm1 ◽  
Mouse Neuroblastoma ◽  
Neuro2a Cells ◽  
Neuronal Functions

AbstractRecently, we demonstrated that the oligosaccharide portion of ganglioside GM1 is responsible, via direct interaction and activation of the TrkA pathway, for the ability of GM1 to promote neuritogenesis and to confer neuroprotection in Neuro2a mouse neuroblastoma cells. Recalling the knowledge that ganglioside GM1 modulates calcium channels activity, thus regulating the cytosolic calcium concentration necessary for neuronal functions, we investigated if the GM1-oligosaccharide would be able to overlap the GM1 properties in the regulation of calcium signaling, excluding a specific role played by the ceramide moiety inserted into the external layer of plasma membrane. We observed, by calcium imaging, that GM1-oligosaccharide administration to undifferentiated Neuro2a cells resulted in an increased calcium influx, which turned out to be mediated by the activation of TrkA receptor. The biochemical analysis demonstrated that PLCγ and PKC activation follows the TrkA stimulation by GM1-oligosaccharide, leading to the opening of calcium channels both on the plasma membrane and on intracellular storages, as confirmed by calcium imaging experiments performed with IP3 receptor inhibitor. Subsequently, we found that neurite elongation in Neuro2a cells was blocked by subtoxic administration of extracellular and intracellular calcium chelators, suggesting that the increase of intracellular calcium is responsible of GM1-oligosaccharide mediated differentiation. These results suggest that GM1-oligosaccharide is responsible for the regulation of calcium signaling and homeostasis at the base of the neuronal functions mediated by plasma membrane GM1.

scholarly journals Cytosolic and nuclear calcium signaling in atrial myocytes: IP3-mediated calcium release and the role of mitochondria

Channels ◽  
2015 ◽  
Vol 9 (3) ◽  
pp. 129-138 ◽  
Author(s):  
Felix Hohendanner ◽  
Joshua T Maxwell ◽  
Lothar A Blatter
Keyword(s):  
Calcium Signaling ◽  
Calcium Release ◽  
Atrial Myocytes ◽  
Nuclear Calcium
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