title: 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.
abstract: OBJECTIVE
  In the heart, a period of ischaemia followed by reperfusion evokes powerful cytosolic Ca(2+) 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 Ca(2+) oscillations that initiate from acidic stores such as lysosomes, likely via two-pore channels (TPCs, TPC1 and 2).
  
  
  RESULTS
  An NAADP antagonist called Ned-K was developed by rational design based on a previously existing scaffold. Ned-K suppressed Ca(2+) 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.
  
  
  CONCLUSIONS
  NAADP signalling plays a major role in reperfusion-induced cell death and represents a potent pathway for protection against reperfusion injury.
authors.affiliation: The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, WC1E 6HX London, UK s.davidson@ucl.ac.uk.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Davidson
authors.affiliation: The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, WC1E 6HX London, UK.
authors.forename: Kirsty
authors.initials: K
authors.lastname: Foote
authors.affiliation: The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, WC1E 6HX London, UK.
authors.forename: Suma
authors.initials: S
authors.lastname: Kunuthur
authors.affiliation: School of Chemistry, University of Southampton, Highfield, Southampton, UK.
authors.forename: Raj
authors.initials: R
authors.lastname: Gosain
authors.affiliation: The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, WC1E 6HX London, UK.
authors.forename: Noah
authors.initials: N
authors.lastname: Tan
authors.affiliation: The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, WC1E 6HX London, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Tyser
authors.affiliation: Department of Physiology, Li Ka Shing School of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Yong Juan
authors.initials: YJ
authors.lastname: Zhao
authors.affiliation: Department of Physiology, Li Ka Shing School of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Richard
authors.initials: R
authors.lastname: Graeff
authors.affiliation: School of Pharmacy, University of East Anglia, Norwich, UK.
authors.forename: A
authors.initials: A
authors.lastname: Ganesan
authors.affiliation: Department of Cell and Developmental Biology, University College London, London, UK.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Duchen
authors.affiliation: Department of Cell and Developmental Biology, University College London, London, UK.
authors.forename: Sandip
authors.initials: S
authors.lastname: Patel
authors.affiliation: The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, WC1E 6HX London, UK.
authors.forename: Derek M
authors.initials: DM
authors.lastname: Yellon
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects*; D002243:Carbolines / Q000494:pharmacology*; D019610:Cytoprotection; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D008933:Mitochondrial Swelling / Q000187:drug effects; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009249:NADP / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D000097903:Two-Pore Channels
chemical_list: D015220:Calcium Channels; D002243:Carbolines; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D009249:NADP; D010879:Piperazines; C539827:1-(3-((4-(2-fluorophenyl)piperazin-1-yl)methyl)-4-methoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido(3,4-b)indole-3-carboxylic acid; C000610585:Ned-K compound; C546784:TPCN1 protein, mouse; D000097903:Two-Pore Channels; C024376:NAADP
keywords: Calcium; Ischaemia; Lysosomes; NAADP; Reperfusion