The human two-pore channel 1 is modulated by cytosolic and luminal calcium

Lagostena, Laura; Festa, Margherita; Pusch, Michael; Carpaneto, Armando

doi:10.1038/srep43900

Cited by 50 publications

(41 citation statements)

References 55 publications

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“…In plant cells, the fast vacuolar channel is inhibited by cytosolic and luminal Ca 2+ and by luminal Mg 2+ . A similar modulation was recently found with the human TPC1 channel . Moreover, the slow vacuolar (SV) channel is down‐regulated by vacuolar Ca 2+ .…”

Section: Discussionsupporting

confidence: 67%

In vitro and in vivo characterization of modulation of the vacuolar cation channel TRPY1 from Saccharomyces cerevisiae

et al. 2018

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Saccharomyces cerevisiae possesses a transient receptor potential (TRP) channel homolog TRPY1 in its vacuolar membrane, considered to be an ancestral TRP channel. So far, studies have focused on the channel properties of TRPY1, but its regulation and physiologic role remained to be elucidated. Here, we investigated TRPY1 channel function in vitro and in vivo. Patch-clamp recording of TRPY1 in yeast vacuolar membranes showed that Ca on the lumen side inhibited TRPY1-mediated channel activity, whereas luminal Zn increased the currents. TRPY1 was activated in the presence of a reducing agent, 2-mercaptoethanol. The cysteine at position 624 was identified as the target for this activating action. This activation was independent of the presence of cytosolic Ca . The amplitude of TRPY1-mediated current was reduced by addition of phosphatidylinositol 3-phosphate on the cytosolic side but not by phosphatidylinositol (PI) or phosphatidylinositol 3,5-phosphate. Measurement of the transient Ca increase in response to hyper-osmotic shock in several yeast mutants defective in different steps of the PI phosphate biogenesis pathway supported this interpretation. Addition of a microtubule inhibitor strongly decreased the transient cytosolic Ca increase upon hyper-osmotic shock. Taken together, the data indicate that the vacuolar TRPY1 Ca channel mediates the perception of cytosolic signals that were induced by external changes in osmolarity, and participates in the modulation of cytosolic calcium signaling through Ca release from the vacuole to maintain intracellular Ca homeostasis in yeast.

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Section: Discussionsupporting

confidence: 67%

In vitro and in vivo characterization of modulation of the vacuolar cation channel TRPY1 from Saccharomyces cerevisiae

et al. 2018

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“…The introduction of Asn630 into AtTPC1 converts it to a channel with a high selectivity for Na + over K + and decreases the relative Ca 2+ permeability 10-fold (Guo et al, 2017). Animal TPCs, depending on their mode of activation (by either an indirect effect of NAADP or binding of PI(3,5)P 2 ), appear either as a Ca 2+ -permeable NSCC (Morgan et al, 2015;Pitt et al, 2016) or as Na + -selective channels with low Ca 2+ permeability (Guo et al, 2017;Lagostena et al, 2017), respectively. AtTPC1 is not responsive to either PI(3,5)P 2 or NAADP (Boccaccio et al, 2014).…”

Section: New Phytologistmentioning

confidence: 99%

Calcium transport across plant membranes: mechanisms and functions

et al. 2018

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Contents Summary 49 I. Introduction 49 II. Physiological and structural characteristics of plant Ca -permeable ion channels 50 III. Ca extrusion systems 61 IV. Concluding remarks 64 Acknowledgements 64 References 64 SUMMARY: Calcium is an essential structural, metabolic and signalling element. The physiological functions of Ca are enabled by its orchestrated transport across cell membranes, mediated by Ca -permeable ion channels, Ca -ATPases and Ca /H exchangers. Bioinformatics analysis has not determined any Ca -selective filters in plant ion channels, but electrophysiological tests do reveal Ca conductances in plant membranes. The biophysical characteristics of plant Ca conductances have been studied in detail and were recently complemented by molecular genetic approaches. Plant Ca conductances are mediated by several families of ion channels, including cyclic nucleotide-gated channels (CNGCs), ionotropic glutamate receptors, two-pore channel 1 (TPC1), annexins and several types of mechanosensitive channels. Key Ca -mediated reactions (e.g. sensing of temperature, gravity, touch and hormones, and cell elongation and guard cell closure) have now been associated with the activities of specific subunits from these families. Structural studies have demonstrated a unique selectivity filter in TPC1, which is passable for hydrated divalent cations. The hypothesis of a ROS-Ca hub is discussed, linking Ca transport to ROS generation. CNGC inactivation by cytosolic Ca , leading to the termination of Ca signals, is now mechanistically explained. The structure-function relationships of Ca -ATPases and Ca /H exchangers, and their regulation and physiological roles are analysed.

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“…65,92,93 TPC1 is broadly localized to recycling endosomes, early and late endosomes, and lysosomes, while TPC2 is localized more with lysosomes. 92,[94][95][96] One fundamental difference between TPC1 and TPC2 is their voltage dependence [97][98][99][100][101][102][103] ; TPC1 is a voltage-gated channel able to be activated by the NAADP, Ca 2+ , and PI(3,5)P 2 , whereas TPC2 is voltage-insensitive.…”

Section: Tpcs and Tat Endolysosome Escapementioning

confidence: 99%

Two‐pore channels regulate Tat endolysosome escape and Tat‐mediated HIV‐1 LTR transactivation

et al. 2020

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Abbreviations: BAPTA-AM, 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid tetrakis(acetoxymethyl ester); CD26, cluster of differentiation 4; CD4+, cluster of differentiation 4; CNS, central nervous system; CRISPR, clustered regularly interspaced short palindromic repeats; CSF, cerebrospinal fluid; CXCR4, C-X-C chemokine receptor type 4; DMEM, Dulbecco's Modified Eagle Medium; FBS, fetal bovine serum; FITC, fluorescein isothiocyanate; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; GFP, green fluorescent protein; gp120, envelope glycoprotein 120; HCl, hydrogen chloride; HIV-1, human immunodeficiency virus-1; kDa, kilodalton; LRP1, low density lipoprotein receptor-related protein 1; LTR, long terminal repeat; MERS-CoV, middle east respiratory syndrome coronavirus; MW, molecular weight; NAADP, nicotinic acid adenine dinucleotide phosphate; P2X4, purinergic P2X4 receptors; PAGE, polyacrylamide gel electrophoresis; PBS, phosphate-buffered saline; PI(3,5)P2, phosphatidylinositol 3,5-bisphosphate; PVDF, polyvinylidene difluoride; RIPA, radioimmunoprecipitation assay buffer; SD, standard deviation; SDS, sodium dodecyl sulfate; shRNA, short hairpin RNA; Tat, transcriptional activator; TFEB, transcription factor EB; TPCs, two-pore channels; Trans-Ned19, (1R,3S)-1- [3][4]piperazin-1-yl] methyl]-4-methoxyphenyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid; TRPM2, transient receptor potential melastatin 2; TRPML1, transient receptor potential mucolipin 1. AbstractHIV-1 Tat is essential for HIV-1 replication and appears to play an important role in the pathogenesis of HIV-associated neurological complications. Secreted from infected or transfected cells, Tat has the extraordinary ability to cross the plasma membrane. In the brain, Tat can be taken up by CNS cells via receptor-mediated endocytosis. Following endocytosis and its internalization into endolysosomes, Tat must be released in order for it to activate the HIV-1 LTR promoter and facilitate HIV-1 viral replication in the nucleus. However, the underlying mechanisms whereby Tat escapes endolysosomes remain unclear. Because Tat disrupts intracellular calcium homeostasis, we investigated the involvement of calcium in Tat endolysosome escape and subsequent LTR transactivation. We demonstrated that chelating endolysosome calcium with high-affinity rhodamine-dextran or chelating cytosolic calcium with BAPTA-AM attenuated Tat endolysosome escape and LTR transactivation.Significantly, we demonstrated that pharmacologically blocking and knocking down the endolysosome-resident two-pore channels (TPCs) attenuated Tat endolysosome escape and LTR transactivation. This calcium-mediated effect appears to be selective for TPCs because knocking down TRPML1 calcium channels was without effect. Our findings suggest that calcium released from TPCs is involved in Tat endolysosome escape and subsequent LTR transactivation. TPCs might represent a novel therapeutic target against HIV-1 infection and HIV-associated neurological complications.

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The human two-pore channel 1 is modulated by cytosolic and luminal calcium

Cited by 50 publications

References 55 publications

In vitro and in vivo characterization of modulation of the vacuolar cation channel TRPY1 from Saccharomyces cerevisiae

In vitro and in vivo characterization of modulation of the vacuolar cation channel TRPY1 from Saccharomyces cerevisiae

Calcium transport across plant membranes: mechanisms and functions

Two‐pore channels regulate Tat endolysosome escape and Tat‐mediated HIV‐1 LTR transactivation

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