Convergent regulation of the lysosomal two-pore channel-2 by Mg2+, NAADP, PI(3,5)P2 and multiple protein kinases

Jha, Archana; Ahuja, Malini; Patel, Sandip; Brǎiloiu, Eugen; Muallem, Shmuel

doi:10.1002/embj.201387035

Cited by 167 publications

(205 citation statements)

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“…There is evidence that TPC1 is mainly present in the proximal endosomal system, and TPC2 is predominantly expressed on late endosomes and lysosomes 16,18,19 . The activation mechanism of TPCs is complex and has been suggested to involve the second messenger nicotinic acid adenine dinucleotide phosphate (NAADP) and the endolysosomal membrane lipidphosphatidylinositol (3,5)bisphosphate (PI(3,5)P 2 ) 17,18,[20][21][22][23][24] . Independent of what the nature of the endogenous ligand of these channels might be, there is substantial evidence that on activation TPCs mediate the release of Ca 2 þ from lysosomal stores.…”

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confidence: 99%

“…Independent of what the nature of the endogenous ligand of these channels might be, there is substantial evidence that on activation TPCs mediate the release of Ca 2 þ from lysosomal stores. Patch-clamp 21,22,24 , lipid bilayer and calcium imaging experiments 18,25,26 indicate that TPCs are Ca 2 þ permeable channels and, hence, may directly confer Ca 2 þ release from endosomes/lysosomes.…”

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confidence: 99%

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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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confidence: 99%

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confidence: 99%

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

et al. 2014

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“…However, evidence from studies in HER2 positive SKBR3 cells do suggest functional TPC channels in this breast cancer cell line [8].…”

Section: Introductionmentioning

confidence: 89%

Differential effects of two-pore channel protein 1 and 2 silencing in MDA-MB-468 breast cancer cells

Jahidin

Stewart

Thompson

et al. 2016

Biochemical and Biophysical Research Communications

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Two-pore channel proteins, TPC1 and TPC2, are calcium permeable ion channels found localized to the membranes of endolysosomal calcium stores. There is increasing interest in the role of TPC-mediated intracellular signaling in various pathologies; however their role in breast cancer has not been extensively evaluated. TPC1 and TPC2 mRNA was present in all non-tumorigenic and tumorigenic breast cell lines assessed. Silencing of TPC2 but not TPC1 attenuated epidermal growth factor-induced vimentin expression in MDA-MB-468 breast cancer cells. This effect was not due to a general inhibition of epithelial to mesenchymal transition (EMT) as TPC2 silencing had no effect on epidermal growth factor (EGF)-induced changes on E-cadherin expression. TPC1 and TPC2 were also shown to differentially regulate cyclopiazonic acid (CPA)-mediated changes in cytosolic free Ca 2+ . These findings indicate potential differential regulation of signaling processes by TPC1 and TPC2 in breast cancer cells. Abbreviations

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“…12 On the other hand, TPC2 has been suggested to be strongly inhibited by Mg 2C ions, which selectively inhibitis outward Na C currents regardless of NAADP or PtdIns(3,5)P2. 15 This inhibition is more effective from the cytoplasmic free Mg 2C than from the luminal face, and small changes in cytoplasmic free Mg 2C markedly affect the activity of TPC2 and thus the lysosomal membrane potential. 15 A decrease in cytoplasmic free Mg 2C is suggested to depolarize the lysosomal membrane potential to affect the transport of all electrogenic coupled and uncoupled transporters, including facilitation of Ca 2C release from the lysosomes.…”

Section: Activity Regulationmentioning

confidence: 98%

“…4 Still, on the other hand, in 2012 and 2013 2 independent studies refuted that mammalian TPCs were Ca 2C release channels activated by NAADP, probing that they are not Ca 2C but Na C release channels that are not activated by NAADP but by phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) and inhibited by the mammalian target of rapamycin (mTOR), 5,6 which caused a great commotion regarding TPCs regulation and function among the scientific community. [7][8][9][10] Nowadays, it is accepted that mammalian TPCs not only function as Ca 2C or Na C release channels, but also as H C and K C channels, 11,12 and it has been demonstrated that TPCs can be activated by other signals apart from NAADP and PI (3,5)P2, such as the leucine-rich repeat kinase 2 (LRRK2) 13 or action potentials, 14 and inhibited by Mg 2C concentrations, 15 Ca 2C and Na C ion channels inhibitors, 16,17 or c-Jun N-terminal kinase (JNK) and p38 kinase, 15 apart from mTOR. So that, it seems reasonable that, according to the cellular context, TPCs could be differentially regulated and exert different functions.…”

Section: Introductionmentioning

confidence: 99%

Two-pore channels (TPCs): Novel voltage-gated ion channels with pleiotropic functions

Feijóo‐Bandín¹,

García-Vence²,

García-Rúa³

et al. 2016

Channels

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Two-pore channels (TPC1-3) comprise a subfamily of the eukaryotic voltage-gated ion channels (VGICs) superfamily that are mainly expressed in acidic stores in plants and animals. TPCS are widespread across the animal kingdom, with primates, mice and rats lacking TPC3, and mainly act as Ca C and Na C channels, although it was also suggested that they could be permeable to other ions. Nowadays, TPCs have been related to the development of different diseases, including Parkinsons disease, obesity or myocardial ischemia. Due to this, their study has raised the interest of the scientific community to try to understand their mechanism of action in order to be able to develop an efficient drug that could regulate TPCs activity. In this review, we will provide an updated view regarding TPCs structure, function and activation, as well as their role in different pathophysiological processes.

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Convergent regulation of the lysosomal two-pore channel-2 by Mg2+, NAADP, PI(3,5)P2 and multiple protein kinases

Cited by 167 publications

References 50 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

Differential effects of two-pore channel protein 1 and 2 silencing in MDA-MB-468 breast cancer cells

Two-pore channels (TPCs): Novel voltage-gated ion channels with pleiotropic functions

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