Molecular mechanisms of endolysosomal Ca2+ signalling in health and disease

Morgan, Anthony J.; Platt, Frances M.; Lloyd-Evans, Emyr; Galione, Antony

doi:10.1042/bj20110949

Cited by 349 publications

(469 citation statements)

References 315 publications

(429 reference statements)

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“…Another attractive hypothesis for impaired endolysosomal trafficking is a defect in vesicle fusion or ARTICLE fission processes. It has been postulated before that Ca 2 þ is required for vesicular fusion processes and thereby regulates trafficking of vesicular cargo proteins 30,32,33 . In accordance with this hypothesis, we found that in WT MEFs chelation of cytosolic Ca 2 þ by 1,2-bis(2-aminophenoxy)ethane-N,N,N 0 ,N 0 -tetraacetic acid tetrakis(acetoxymethyl ester) (BAPTA-AM) mimics the effect on EGF trafficking observed in TPC2 À / À MEFs (Fig.…”

Section: Articlementioning

confidence: 99%

High susceptibility to fatty liver disease in two-pore channel 2-deficient mice

et al. 2014

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Endolysosomal organelles play a key role in trafficking, breakdown and receptor-mediated recycling of different macromolecules such as low-density lipoprotein (LDL)-cholesterol, epithelial growth factor (EGF) or transferrin. Here we examine the role of two-pore channel (TPC) 2, an endolysosomal cation channel, in these processes. Embryonic mouse fibroblasts and hepatocytes lacking TPC2 display a profound impairment of LDL-cholesterol and EGF/EGF-receptor trafficking. Mechanistically, both defects can be attributed to a dysfunction of the endolysosomal degradation pathway most likely on the level of late endosome to lysosome fusion. Importantly, endolysosomal acidification or lysosomal enzyme function are normal in TPC2-deficient cells. TPC2-deficient mice are highly susceptible to hepatic cholesterol overload and liver damage consistent with non-alcoholic fatty liver hepatitis. These findings indicate reduced metabolic reserve of hepatic cholesterol handling. Our results suggest that TPC2 plays a crucial role in trafficking in the endolysosomal degradation pathway and, thus, is potentially involved in the homoeostatic control of many macromolecules and cell metabolites.

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Section: Articlementioning

confidence: 99%

High susceptibility to fatty liver disease in two-pore channel 2-deficient mice

et al. 2014

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“…Voltage-gated calcium channels (VGCCs) are found in excitable cells (e.g., glial cells, muscle, neurons, etc.) [3][4][5][6]. There are at least six classes of VGCCs (L-, N-, P/Q-, R-and the T-type channels) that are distributed according to cell type and location, and that may be distinguished by electrophysiological, pharmacological, and structural characteristics.…”

Section: Introductionmentioning

confidence: 99%

Voltage-Gated Calcium Channel Antagonists: Potential Analgesics for Jejunal Pains

Feliks¹,

Wrońska²

2017

Pain Relief - From Analgesics to Alternative Therapies

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The significant role of voltage-gated calcium channel (VGCC) L-type antagonists used concomitantly with opioids in attenuation of clinical pain has been confirmed. The aim of this study is to evaluate the comparable effect of intracerebroventricularly (i.c.v.) administered diltiazem, nifedipine and/or verapamil -specific antagonists of VGCCsin the dose of 1.0 and 2.0 mg in toto on behavioral signs, clinical symptoms, rumen motor activity and biochemical (plasma cortisol and catecholamine-CA) parameters in sheep that have undergone experimental duodenal distension (DD) and to determine whether voltage-gated calcium channel inhibitors (VGCCIs) exert any anti-nociceptive effects under these conditions. The study was carried out using 24 mature, behind reproductive season crossbred ewes, each weighing 32-42 kg. DD was managed by inclusion and the distension of stretching balloon (having 40 mL of water 39°C temperature-DD40). After 5 min of DD40, the signs were observed: an important augmentation of behavioral nociceptive signs, particularly looking around, defecation, head movement, stretching, grinding, lying down, tachycardia, hyperventilation, inhibition of ruminal contractions (70% approximately, during 15 min) and an increase in plasma catecholamine concentration (over sevenfold increase of epinephrine (E): from 0.24 ± 0.12 in control to 2.98 ± 0.21 mM L −1 during 2 h following DD, 2-times norepinephrine (NE): from 1.29 ± 0.23 in control to 2.51 ± 0.30 mM L −1 and 124% increase of dopamine (DA): from 0.94 ± 0.02 in control to 2.10 ± 0.35 mM L −1 ). VGCCI infusion administered 10 min before duodenal distension diminished severity of jejunal nociceptive reactions, for instance, behavioral symptoms, cardiac acceleration, increase in the number of respiration, inhibition of the reticulum and rumen hypomotility, and effortlessly abolished the increasing presence of plasma cortisol and biogenic amines (CA) release. We suggest that the increase and insistence of visceral hyperalgesia stimulate the flow of Ca 2+ ion flow, provoking neurohormones/neuromediators liberatione and cytoplasmic membrane responsiveness modulation. This result confirmed analgesic effects of VGCCIs L-and/or R-type (nimodipine, lercanidipine, SNX-482) obtained by other authors and also suggests that these channels play a crucial role in the modulation of acute visceral hyperalgesia in sheep and may be a therapeutic target for new drugs.

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“…There are many hypotheses about the mechanisms of NAADP action. Much evidence suggests that NAADP induces small yet localized cytoplasmic Ca 2+ -signals subsequently amplified into regenerative global Ca 2+ -signals by recruitment of endoplasmic reticulum via calcium-induced calcium release (CICR) [17]. The actual data collected on the NAADP-receptors remain disputable.…”

Section: Resultsmentioning

confidence: 99%

“…The actual data collected on the NAADP-receptors remain disputable. The potential NAADP-sensitive Ca 2+ -channels candidates include TRPML1, TRPM2, TPCs and even RyRs [16,17]. In order to investigate the effects of NAADP in the cell, there was synthesized the selective antagonist of NAADP -NED-19.…”

Section: Resultsmentioning

confidence: 99%

Influence of taurolithocholate 3-sulphate on calcium content in cytosol and store of isolated mice hepatocytes

Bychkova¹

2015

Biol. Stud.

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Momohydroxylated bile acids, including taurolitocholate (TLC) and its 3-sulphate (TLC-S), have been shown to increase [Ca 2+ ] i in cytosol of rat hepatocytes [1,2]. These bile acids mobilize Ca 2+ from the internal pool which is sensitive to inositol trisphosphate (IP 3 ). However, bile-acid mediated Ca 2+ release is independent of IP 3 production. Nicotinic acid adenine dinucleotide phosphate (NAADP) is a nucleotide which can to release calcium from specific type of intracellular store defined as endo-lysosomal system or acidic store. The aim of this study was to examine influence of NED-19 (antagonist of NAADP) on TLC-S-induced change of calcium content in cytosol of and endoplasmic reticulum of isolated mice hepatocytes in order to elucidate the role of acidic store in bile-acid mediated Ca 2+ release. Isolated hepatocytes of mice were loaded with fluo-4 (2.5 µM). Fluorescent images were obtained using Leica SP2 MP dual two-photon confocal microscope. Isolated hepatocytes were permeabilized in suspension with saponine (0.1 mg/mL). Next the permeabilized suspension of hepatocytes was loaded with Mag-Fura-2 AM (5 µM). Measurement of Ca2+ content in store of permeabilized cells was conducted using spectrofluorimetric method. We confirmed that TLC-S (50, 100 and 200 µM) elicited cytosolic Ca 2+ -signals, which were not inhibited by the IP 3 -receptors (IP 3 Rs) antagonist 2-APB (100 µM). In suspensions of permeabilized murine hepatocytes TLC-S (100 µM) mobilized 66.10 ± 8.87 % of the total stored calcium as detected by ionomycin-induced release (10 µM). After application of TLC-S thapsigargin could release only 47.94 ± 3.05 %. Previous addition of NED-19 (100 nM) decreased fraction of calcium that is released by TLC-S and equals 33.25 ± 2.15 % of the total calcium. In this case, the following use of thapsigargin mobilized only 21.75 ± 10.68 %. Thus, previous application of NED-19 significantly (n = 6; P ≤ 0.01) reduced the proportion of calcium released by TLC-S 2-fold. It was observed that the rate of TLC-S-induced decrease of calcium content in the intracellular store was 1.8 times slower than after application of NED-19 (n = 6; Р ≤ 0.05). Previous application of NED-19 increased the rate of thapsigargin-evoked calcium content reduction by a factor of 2.5 (n = 6; Р ≤ 0.01). We suggest the impact of acid store in TLC-Selicited cytosolic Ca 2+ -signals in mice hepatocytes. Thus, the mechanism of TLC-S-induced calcium release is also NAADP-mediated.

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Molecular mechanisms of endolysosomal Ca2+ signalling in health and disease

Cited by 349 publications

References 315 publications

High susceptibility to fatty liver disease in two-pore channel 2-deficient mice

High susceptibility to fatty liver disease in two-pore channel 2-deficient mice

Voltage-Gated Calcium Channel Antagonists: Potential Analgesics for Jejunal Pains

Influence of taurolithocholate 3-sulphate on calcium content in cytosol and store of isolated mice hepatocytes

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