Calcium signals regulated by NAADP and two-pore channels - their role in development, differentiation and cancer

Parrington, John; Lear, Pamela; Hachem, A

doi:10.1387/ijdb.150211jp

Cited by 15 publications

(8 citation statements)

References 148 publications

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“…These new data support our previous findings that localized TPC2-mediated Ca 2+ release might act upstream of more widespread Ca 2+ release from IP 3 Rs (predominantly during SP1) and RyRs (predominantly during SP2). Our new data also support the trigger hypothesis of NAADP-mediated Ca 2+ signaling, and the role of TPC2 as an upstream regulator of the ER/SR-residing IP 3 Rs and RyRs (Cancela et al, 1999; Kinnear et al, 2004, 2008; Patel et al, 2010; Galione, 2011; Kelu et al, 2015; Parrington et al, 2015). The contrasting roles of the ER/SR-Ca 2+ channels during myogenesis have previously been demonstrated in C2C12 myoblasts, where IP 3 R-mediated signaling has been shown to play a role in differentiation (Porter et al, 2002), whereas RyR-mediated signaling is not necessary for the early events (even though RyR are expressed in C2C12 cells at this stage), but it is involved in EC-coupling in the mature skeletal muscle (Aley et al, 2010).…”

Section: Discussionsupporting

confidence: 83%

“…There is a growing interest in the role played by two-pore channels (TPCs) and their link with nicotinic acid adenine dinucleotide diphosphate (NAADP) signaling with regards to their combinatorial contribution to the Ca 2+ -mediated regulation of differentiation and development (Calcraft et al, 2009; Patel et al, 2010; Galione, 2011; Morgan and Galione, 2014; Parrington and Tunn, 2014; Parrington et al, 2015; Brailoiu and Brailoiu, 2016). The various roles played by the Ca 2+ mobilizing messengers inositol 1,4,5-trisphosphate (IP 3 ) and cyclic adenosine diphosphate ribose (cADPR), and their respective receptors in the endoplasmic/sarcoplasmic reticulum (ER/SR) membrane, are well established (Berridge, 1993; Lee, 1993; Berridge et al, 2003; Mikoshiba, 2007; Lanner et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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Ca 2+ release via two-pore channel type 2 (TPC2) is required for slow muscle cell myofibrillogenesis and myotomal patterning in intact zebrafish embryos

Kelu

Webb

Parrington

et al. 2017

Developmental Biology

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We recently demonstrated a critical role for two-pore channel type 2 (TPC2)-mediated Ca release during the differentiation of slow (skeletal) muscle cells (SMC) in intact zebrafish embryos, via the introduction of a translational-blocking morpholino antisense oligonucleotide (MO). Here, we extend our study and demonstrate that knockdown of TPC2 with a non-overlapping splice-blocking MO, knockout of TPC2 (via the generation of a tpcn2 mutant line of zebrafish using CRISPR/Cas9 gene-editing), or the pharmacological inhibition of TPC2 action with bafilomycin A1 or trans-ned-19, also lead to a significant attenuation of SMC differentiation, characterized by a disruption of SMC myofibrillogenesis and gross morphological changes in the trunk musculature. When the morphants were injected with tpcn2-mRNA or were treated with IP/BM or caffeine (agonists of the inositol 1,4,5-trisphosphate receptor (IPR) and ryanodine receptor (RyR), respectively), many aspects of myofibrillogenesis and myotomal patterning (and in the case of the pharmacological treatments, the Ca signals generated in the SMCs), were rescued. STED super-resolution microscopy revealed a close physical relationship between clusters of RyR in the terminal cisternae of the sarcoplasmic reticulum (SR), and TPC2 in lysosomes, with a mean estimated separation of ~52-87nm. Our data therefore add to the increasing body of evidence, which indicate that localized Ca release via TPC2 might trigger the generation of more global Ca release from the SR via Ca-induced Ca release.

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Section: Discussionsupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Ca 2+ release via two-pore channel type 2 (TPC2) is required for slow muscle cell myofibrillogenesis and myotomal patterning in intact zebrafish embryos

Kelu

Webb

Parrington

et al. 2017

Developmental Biology

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“…A recent study showed that most iron in cortical neurons is located in microsomal fractions containing the endoplasmic reticulum and vesicles (Reinert et al, 2019), suggesting that the endolysosomal system is a major iron storage site in cortical neurons, and efflux of iron from these stores can impact neuronal homeostasis. Morphine may promote iron efflux through several endolysosomal conduits, including DMT-1 (Gunshin et al, 1997), two-pore channels (Parrington et al, 2015), and TRPML1 (Dong et al, 2008; Bae et al, 2014). TRPML1 regulates endolysosomal function by releasing cations from endolysosomes, most notably calcium and iron (Dong et al, 2008; Shen et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Morphine-Induced Modulation of Endolysosomal Iron Mediates Upregulation of Ferritin Heavy Chain in Cortical Neurons

Nash

Tarn

Irollo

et al. 2019

eNeuro

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HIV-associated neurocognitive disorders (HAND) remain prevalent and are aggravated by µ-opioid use. We have previously shown that morphine and other µ-opioids may contribute to HAND by inhibiting the homeostatic and neuroprotective chemokine receptor CXCR4 in cortical neurons, and this novel mechanism depends on upregulation of the protein ferritin heavy chain (FHC). Here, we examined the cellular events and potential mechanisms involved in morphine-mediated FHC upregulation using rat cortical neurons of either sex in vitro and in vivo. Morphine dose dependently increased FHC protein levels in primary neurons through µ-opioid receptor (µOR) and Gαi-protein signaling. Cytoplasmic FHC levels were significantly elevated, but nuclear FHC levels and FHC gene expression were unchanged. Morphine-treated rats also displayed increased FHC levels in layer 2/3 neurons of the prefrontal cortex. Importantly, both in vitro and in vivo FHC upregulation was accompanied by loss of mature dendritic spines, which was also dependent on µOR and Gαi-protein signaling. Moreover, morphine upregulated ferritin light chain (FLC), a component of the ferritin iron storage complex, suggesting that morphine altered neuronal iron metabolism. Indeed, prior to FHC upregulation, morphine increased cytoplasmic labile iron levels as a function of decreased endolysosomal iron. In line with this, chelation of endolysosomal iron (but not extracellular iron) blocked morphine-induced FHC upregulation and dendritic spine reduction, whereas iron overloading mimicked the effect of morphine on FHC and dendritic spines. Overall, these data demonstrate that iron mediates morphine-induced FHC upregulation and consequent dendritic spine deficits and implicate endolysosomal iron efflux to the cytoplasm in these effects.

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“…Links between TPCs and cancer have been summarized in a recent review by Parrington et al (2015) [ 37 ]. In addition, Nguyen et al [ 13 ] have recently shown that TPCs play a crucial role in cancer cell migration and tumor cell dissemination, as silencing TPC1 and TPC2 with siRNA or pharmacological inhibition reduces the adhesion and migration of invasive tumor cells and the formation of lung metastases in an in vivo mouse model.…”

Section: Tpcs and Cancermentioning

confidence: 99%

Endolysosomal Cation Channels and Cancer—A Link with Great Potential

2018

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The endolysosomal system (ES) consists of lysosomes; early, late, and recycling endosomes; and autophagosomes. It is a key regulator not only of macromolecule degradation and recycling, plasma membrane repair, homeostasis, and lipid storage, but also of antigen presentation, immune defense, cell motility, cell death signaling, tumor growth, and cancer progression. In addition, it plays a critical role in autophagy, and the autophagy-lysosome pathway is intimately associated with the hallmarks of cancer, such as escaping cell death pathways, evading immune surveillance, and deregulating metabolism. The function of endolysosomes is critically dependent on both soluble and endolysosomal membrane proteins such as ion channels and transporters. Cation channels found in the ES include members of the TRP (transient receptor potential) channel superfamily, namely TRPML channels (mucolipins) as well as two-pore channels (TPCs). In recent studies, these channels have been found to play crucial roles in endolysosomal trafficking, lysosomal exocytosis, and autophagy. Mutation or loss of these channel proteins can impact multiple endolysosomal trafficking pathways. A role for TPCs in cancer cell migration and metastasis, linked to distinct defects in endolysosomal trafficking such as integrin trafficking, has been recently established. In this review, we give an overview on the function of lysosomes in cancer with a particular focus on the roles which TPCs and TRPML channels play in the ES and how this can affect cancer cells.

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Calcium signals regulated by NAADP and two-pore channels - their role in development, differentiation and cancer

Abstract: ABSTRACT

Cited by 15 publications

References 148 publications

Ca 2+ release via two-pore channel type 2 (TPC2) is required for slow muscle cell myofibrillogenesis and myotomal patterning in intact zebrafish embryos

Ca 2+ release via two-pore channel type 2 (TPC2) is required for slow muscle cell myofibrillogenesis and myotomal patterning in intact zebrafish embryos

Morphine-Induced Modulation of Endolysosomal Iron Mediates Upregulation of Ferritin Heavy Chain in Cortical Neurons

Endolysosomal Cation Channels and Cancer—A Link with Great Potential

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