The drug praziquantel (PZQ) has served as the long-standing drug therapy for treatment of infections caused by parasitic flatworms. These encompass diseases caused by parasitic blood, lung, and liver ...flukes, as well as various tapeworm infections. Despite a history of clinical usage spanning over 4 decades, the parasite target of PZQ has long resisted identification. However, a flatworm transient receptor potential ion channel from the melastatin subfamily (TRPMPZQ) was recently identified as a target for PZQ action. Here, recent experimental progress interrogating TRPMPZQ is evaluated, encompassing biochemical, pharmacological, genetic, and comparative phylogenetic data that highlight the properties of this ion channel. Various lines of evidence that support TRPMPZQ being the therapeutic target of PZQ are presented, together with additional priorities for further research into the mechanism of action of this important clinical drug.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Two-pore channels (TPCs) are ancient members of the voltage-gated ion channel superfamily that localize to acidic organelles such as lysosomes. The TPC complex is the proposed target of the ...Ca2+-mobilizing messenger NAADP, which releases Ca2+ from these acidic Ca2+ stores. Whereas details of TPC activation and native ion permeation remain unclear, a consensus has emerged around their function in regulating endolysosomal trafficking. This role is supported by recent proteomic data showing that TPCs interact with proteins controlling membrane organization and dynamics, including Rab GTPases and components of the fusion apparatus. Regulation of TPCs by PtdIns(3,5)P2 and/or NAADP (nicotinic acid adenine dinucleotide phosphate) together with their functional and physical association with Rab proteins provides a mechanism for coupling phosphoinositide and trafficking protein cues to local ion fluxes. Therefore, TPCs work at the regulatory cross-roads of (patho)physiological cues to co-ordinate and potentially deregulate traffic flow through the endolysosomal network. This review focuses on the native role of TPCs in trafficking and their emerging contributions to endolysosomal trafficking dysfunction.
Ca2+ Signaling and Regeneration Marchant, Jonathan S
Cold Spring Harbor perspectives in biology,
11/2019, Volume:
11, Issue:
11
Journal Article
Peer reviewed
Open access
Regeneration is the process by which lost or damaged tissue is replaced in adult organisms. Some organisms exhibit robust regenerative capabilities, while others, including humans, do not. ...Understanding the molecular principles governing the regenerative malleability of different organisms is of fundamental biological interest. Further, this problem has clear impact for the field of "regenerative medicine," which aspires to understand how human cells, tissues, and organs may be restored to normal function in scenarios of disease, damage, or age-related decline. This review will focus on the planarian flatworm as a powerful model system for studying the role of Ca2+ signals in regeneration. These invertebrate animals display an astounding innate regenerative capacity capable of regenerating complete organisms from tiny, excised fragments. New knowledge and methodological capabilities in this system highlight the potential for studying the role of Ca2+ signaling at multiple stages of the regenerative blueprint that controls stem cell behavior in vivo.
Infections caused by parasitic flatworms impose a considerable worldwide health burden. One of the most impactful is schistosomiasis, a disease caused by parasitic blood flukes. Treatment of ...schistosomiasis has relied on a single drug – praziquantel (PZQ) – for decades. The utility of PZQ as an essential medication is, however, intertwined with a stark gap in our knowledge as to how this drug works. No flatworm target has been identified that readily explains how PZQ paralyzes and damages schistosomes. Recently, a schistosome ion channel was discovered that is activated by PZQ and displays characteristics which mirror key features of PZQ action on schistosomes. Here, the journey to discovery of this target, properties of this ion channel, and remaining questions are reviewed.
The anthelmintic drug PZQ is the key drug for treating schistosomiasis and several other diseases caused by parasitic flatworms.Despite decades of clinical usage, no flatworm target for PZQ has been convincingly defined – a long-standing roadblock in this field.A calcium-permeable ion channel in Schistosoma mansoni, activated by PZQ, has recently been identified. The characteristics of this channel mirror key features of PZQ action on schistosome muscle.This ion channel is a member of the transient receptor potential melastatin (TRPM) channel subfamily which is broadly expressed in PZQ-sensitive flatworms.This discovery will help to decipher how PZQ perturbs schistosome calcium homeostasis and the ensuing relevance to clinical activity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
•Many viruses co-opt host-cell endocytic pathways as a conduit into the cell.•TPCs and TRPMLs are endolysosomal Ca2+ channels which regulate endocytic trafficking.•Molecular or pharmacological ...inhibition of TPCs or TRPMLs inhibits virus entry.•Gaps in mechanistic understanding of how TPCs and TRPMLs regulate viral entry are highlighted.•Novel small molecule drugs enable development of TPCs and TRPMLs as antiviral targets.
Many viruses exploit host-cell Ca2+ signaling processes throughout their life cycle. This is especially relevant for viruses that translocate through the endolysosomal system, where cellular infection is keyed to the microenvironment of these acidic Ca2+ stores and Ca2+-dependent trafficking pathways. As regulators of the endolysosomal ionic milieu and trafficking dynamics, two families of endolysosomal Ca2+-permeable cation channels – two pore channels (TPCs) and transient receptor potential mucolipins (TRPMLs) – have emerged as important host-cell factors in viral entry. Here, we review: (i) current evidence implicating Ca2+ signaling in viral translocation through the endolysosomal system, (ii) the roles of these ion channels in supporting cellular infection by different viruses, and (iii) areas for future research that will help define the potential of TPC and TRPML ligands as progressible antiviral agents.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
6.
Ca 2+ Signaling and Regeneration Marchant, Jonathan S
Cold Spring Harbor perspectives in biology,
11/2019, Volume:
11, Issue:
11
Journal Article
Peer reviewed
Regeneration is the process by which lost or damaged tissue is replaced in adult organisms. Some organisms exhibit robust regenerative capabilities, while others, including humans, do not. ...Understanding the molecular principles governing the regenerative malleability of different organisms is of fundamental biological interest. Further, this problem has clear impact for the field of "regenerative medicine," which aspires to understand how human cells, tissues, and organs may be restored to normal function in scenarios of disease, damage, or age-related decline. This review will focus on the planarian flatworm as a powerful model system for studying the role of Ca
signals in regeneration. These invertebrate animals display an astounding innate regenerative capacity capable of regenerating complete organisms from tiny, excised fragments. New knowledge and methodological capabilities in this system highlight the potential for studying the role of Ca
signaling at multiple stages of the regenerative blueprint that controls stem cell behavior in vivo.
Display omitted
•Nicotinic acid adenine dinucleotide phosphate (NAADP) releases Ca2+ from acidic organelles.•Middle East Respiratory Syndrome coronavirus (MERS-CoV) traffics through host-cell acidic ...organelles.•Blockers of NAADP action inhibited pseudotyped MERS-CoV infectivity.•Knockdown of two-pore channels (TPCs), a target of NAADP, also blocked MERS-CoV infectivity.
Middle East Respiratory Syndrome coronavirus (MERS-CoV) infections are associated with a significant mortality rate, and existing drugs show poor efficacy. Identifying novel targets/pathways required for MERS infectivity is therefore important for developing novel therapeutics. As an enveloped virus, translocation through the endolysosomal system provides one pathway for cellular entry of MERS-CoV. In this context, Ca2+-permeable channels within the endolysosomal system regulate both the luminal environment and trafficking events, meriting investigation of their role in regulating processing and trafficking of MERS-CoV. Knockdown of endogenous two-pore channels (TPCs), targets for the Ca2+ mobilizing second messenger NAADP, impaired infectivity in a MERS-CoV spike pseudovirus particle translocation assay. This effect was selective as knockdown of the lysosomal cation channel mucolipin-1 (TRPML1) was without effect. Pharmacological inhibition of NAADP-evoked Ca2+ release using several bisbenzylisoquinoline alkaloids also blocked MERS pseudovirus translocation. Knockdown of TPC1 (biased endosomally) or TPC2 (biased lysosomally) decreased the activity of furin, a protease which facilitates MERS fusion with cellular membranes. Pharmacological or genetic inhibition of TPC1 activity also inhibited endosomal motility impairing pseudovirus progression through the endolysosomal system. Overall, these data support a selective, spatially autonomous role for TPCs within acidic organelles to support MERS-CoV translocation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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.
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BFBNIB, NUK, PNG, UL, UM, UPUK
Intestinal absorption of vitamin C in humans is mediated via the sodium-dependent vitamin C transporters (hSVCT1 and hSVCT2). hSVCT1 and hSVCT2 are localized at the apical and basolateral membranes, ...respectively, of polarized intestinal epithelia. Studies have identified low plasma levels of vitamin C and decreased expression of hSVCT1 in patients with several inflammatory conditions including inflammatory bowel disease (IBD). Investigating the underlying mechanisms responsible for regulating hSVCT1 expression are critical for understanding vitamin C homeostasis, particularly in conditions where suboptimal vitamin C levels detrimentally affect human health. Previous research has shown that hSVCT1 expression is regulated at the transcriptional level, however, little is known about epigenetic regulatory pathways that modulate hSVCT1 expression in the intestine. In this study, we found that hSVCT1 expression and function were significantly decreased in intestinal epithelial cells by the histone deacetylase inhibitors (HDACi), valproic acid (VPA), and sodium butyrate (NaB). Further, expression of transcription factor HNF1α, which is critical for SLC23A1 promoter activity, was significantly down regulated in VPA-treated cells. Chromatin immunoprecipitation (ChIP) assays showed significantly increased enrichment of tetra-acetylated histone H3 and H4 within the SLC23A1 promoter following VPA treatment. In addition, knockdown of HDAC isoforms two, and three significantly decreased hSVCT1 functional expression. Following VPA administration to mice, functional expression of SVCT1 in the jejunum was significantly decreased. Collectively, these in vitro and in vivo studies demonstrate epigenetic regulation of SVCT1 expression in intestinal epithelia partly mediated through HDAC isoforms two and three.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Praziquantel (PZQ) is an essential medicine for treating parasitic flatworm infections such as schistosomiasis, which afflicts over 250 million people. However, PZQ is not universally effective, ...lacking activity against liver flukes of the
genus. The reason for this insensitivity is unclear, as the mechanism of PZQ action is unknown. Here, we use ligand- and target-based methods to demonstrate that PZQ activates a transient receptor potential melastatin ion channel (TRPM
) in schistosomes by engaging a hydrophobic ligand binding pocket within the voltage sensor–like domain of the channel to cause calcium entry and worm paralysis. PZQ activates TRPM
homologs in other PZQ-sensitive flukes, but not
. However, a single amino acid change in the
TRPM
binding pocket, to mimic schistosome TRPM
, confers PZQ sensitivity. After decades of clinical use, the molecular basis of PZQ action at a druggable TRP channel is resolved.
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