title: An NAADP-gated two-pore channel targeted to the plasma membrane uncouples triggering from amplifying Ca2+ signals.
abstract: Nicotinic acid adenine dinucleotide phosphate (NAADP) is a ubiquitous messenger proposed to stimulate Ca(2+) release from acidic organelles via two-pore channels (TPCs). It has been difficult to resolve this trigger event from its amplification via endoplasmic reticulum Ca(2+) stores, fuelling speculation that archetypal intracellular Ca(2+) channels are the primary targets of NAADP. Here, we redirect TPC2 from lysosomes to the plasma membrane and show that NAADP evokes Ca(2+) influx independent of ryanodine receptors and that it activates a Ca(2+)-permeable channel whose conductance is reduced by mutation of a residue within a putative pore. We therefore uncouple TPC2 from amplification pathways and prove that it is a pore-forming subunit of an NAADP-gated Ca(2+) channel.
authors.affiliation: Department of Pharmacology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
authors.forename: Eugen
authors.initials: E
authors.lastname: Brailoiu
authors.forename: Taufiq
authors.initials: T
authors.lastname: Rahman
authors.forename: Dev
authors.initials: D
authors.lastname: Churamani
authors.forename: David L
authors.initials: DL
authors.lastname: Prole
authors.forename: G Cristina
authors.initials: GC
authors.lastname: Brailoiu
authors.forename: Robert
authors.initials: R
authors.lastname: Hooper
authors.forename: Colin W
authors.initials: CW
authors.lastname: Taylor
authors.forename: Sandip
authors.initials: S
authors.lastname: Patel
mesh_terms: D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology*; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009249:NADP / Q000031:analogs & derivatives* / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism; D000097903:Two-Pore Channels
chemical_list: D002118:Calcium; D015220:Calcium Channels; D009249:NADP; D019837:Ryanodine Receptor Calcium Release Channel; C407357:TPCN1 protein, human; D000097903:Two-Pore Channels; C530224:TPCN2 protein, human; C024376:NAADP