TPC1 Knockout Knocks Out TPC1

Hooper, Robert; Churamani, Dev; Davidson, Sean M.; Lin-Moshier, Yaping; Walseth, Timothy F.; Patel, Sandip; Marchant, Jonathan S.

doi:10.1128/mcb.00020-15

Cited by 5 publications

(5 citation statements)

References 18 publications

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“…injection of 160 mg/kg pentobarbitone. Male C57BL/6J and TPC1 knockout mice 33 , 34 were anaesthetized by i.p. injection (0.01 mL/g) of a solution containing ketamine 10 mg/mL, xylazine 2 mg/mL, and atropine 0.06 mg/mL.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of NAADP signalling on reperfusion protects the heart by preventing lethal calcium oscillations via two-pore channel 1 and opening of the mitochondrial permeability transition pore

et al. 2015

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AimsIn the heart, a period of ischaemia followed by reperfusion evokes powerful cytosolic Ca2+ oscillations that can cause lethal cell injury. These signals represent attractive cardioprotective targets, but the underlying mechanisms of genesis are ill-defined. Here, we investigated the role of the second messenger nicotinic acid adenine dinucleotide phosphate (NAADP), which is known in several cell types to induce Ca2+ oscillations that initiate from acidic stores such as lysosomes, likely via two-pore channels (TPCs, TPC1 and 2).Methods and resultsAn NAADP antagonist called Ned-K was developed by rational design based on a previously existing scaffold. Ned-K suppressed Ca2+ oscillations and dramatically protected cardiomyocytes from cell death in vitro after ischaemia and reoxygenation, preventing opening of the mitochondrial permeability transition pore. Ned-K profoundly decreased infarct size in mice in vivo. Transgenic mice lacking the endo-lysosomal TPC1 were also protected from injury.ConclusionNAADP signalling plays a major role in reperfusion-induced cell death and represents a potent pathway for protection against reperfusion injury.

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Section: Methodsmentioning

confidence: 99%

Inhibition of NAADP signalling on reperfusion protects the heart by preventing lethal calcium oscillations via two-pore channel 1 and opening of the mitochondrial permeability transition pore

et al. 2015

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“…Non-alcoholic fatty liver disease (NAFLD) is the most common chronic disorder of the liver characterised by fat accumulation and fibrosis. NAADP is detectable in hepatocytes [ 56 ], liver homogenates bind NAADP [ 7 ] and expression of both TPC1 and TPC2 protein has been validated in the liver using knock-out samples [ 35 , 57 ]. Grimm et al analysed TPC2 knock-out mice and reported several phenotypes consistent with NAFLD [ 35 ].…”

Section: Non-alcoholic Fatty Liver Diseasementioning

confidence: 99%

Two-pore channels and disease

Patel

Kilpatrick

2018

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Two-pore channels (TPCs) are Ca2+-permeable endo-lysosomal ion channels subject to multi-modal regulation. They mediate their physiological effects through releasing Ca2+ from acidic organelles in response to cues such as the second messenger, NAADP. Here, we review emerging evidence linking TPCs to disease. We discuss how perturbing both local and global Ca2+ changes mediated by TPCs through chemical and/or molecular manipulations can induce or reverse disease phenotypes. We cover evidence from models of Parkinson's disease, non-alcoholic fatty liver disease, Ebola infection, cancer, cardiac dysfunction and diabetes. A need for more drugs targeting TPCs is identified.

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“…Alternatively, if truncated TPCs are expressed then this might indicate a requirement for the N-termini of TPCs in PI(3,5)P 2 action. Certainly, documentation of TPC transcripts and protein abundance in the various animals used in the field, including the "knockouts," would be a welcome addition to the literature (64). Finally, insensitivity of TPCs to NAADP might reflect loss of crucial accessory factors.…”

Section: Controversymentioning

confidence: 99%

Function and dysfunction of two-pore channels

2015

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Two-pore channels (TPCs) are evolutionarily important members of the voltage-gated ion channel superfamily. TPCs localize to acidic Ca(2+) stores within the endolysosomal system. Most evidence indicate that TPCs mediate Ca(2+) signals through the Ca(2+)-mobilizing messenger nicotinic acid adenine dinucleotide phosphate (NAADP) to control a range of Ca(2+)-dependent events. Recent studies clarify the mechanism of TPC activation and identify roles for TPCs in disease, highlighting the regulation of endolysosomal membrane traffic by local Ca(2+) fluxes. Chemical targeting of TPCs to maintain endolysosomal "well-being" may be beneficial in disorders as diverse as Parkinson's disease, fatty liver disease, and Ebola virus infection.

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TPC1 Knockout Knocks Out TPC1

Cited by 5 publications

References 18 publications

Inhibition of NAADP signalling on reperfusion protects the heart by preventing lethal calcium oscillations via two-pore channel 1 and opening of the mitochondrial permeability transition pore

Inhibition of NAADP signalling on reperfusion protects the heart by preventing lethal calcium oscillations via two-pore channel 1 and opening of the mitochondrial permeability transition pore

Two-pore channels and disease

Function and dysfunction of two-pore channels

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