title: Two-pore channels: Regulation by NAADP and customized roles in triggering calcium signals.
abstract: NAADP is a potent regulator of cytosolic calcium levels. Much evidence suggests that NAADP activates a novel channel located on an acidic (lysosomal-like) calcium store, the mobilisation of which results in further calcium release from the endoplasmic reticulum. Here, we discuss the recent identification of a family of poorly characterized ion channels (the two-pore channels) as endo-lysosomal NAADP receptors. The generation of calcium signals by these channels is likened to those evoked by depolarisation during excitation-contraction coupling in muscle. We discuss the idea that two-pore channels can mediate a trigger release of calcium which is then amplified by calcium-induced calcium release from the endoplasmic reticulum. This is similar to the activation of voltage-sensitive calcium channels and subsequent mobilisation of sarcoplasmic reticulum calcium stores in cardiac tissue. We suggest that two-pore channels may physically interact with ryanodine receptors to account for more direct release of calcium from the endoplasmic reticulum in analogy with the conformational coupling of voltage-sensitive calcium channels and ryanodine receptors in skeletal muscle. Interaction of two-pore channels with other calcium release channels likely occurs between stores "trans-chatter" and possibly within the same store "cis-chatter". We also speculate that trafficking of two-pore channels through the endo-lysosomal system facilitates interactions with calcium entry channels. Strategic placing of two-pore channels thus provides a versatile means of generating spatiotemporally complex cellular calcium signals.
authors.affiliation: Department of Cell and Developmental Biology, University College London, UK. patel.s@ucl.ac.uk
authors.forename: Sandip
authors.initials: S
authors.lastname: Patel
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Marchant
authors.forename: Eugen
authors.initials: E
authors.lastname: Brailoiu
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D007473:Ion Channels / Q000378:metabolism* / Q000502:physiology; D009249:NADP / Q000031:analogs & derivatives* / Q000494:pharmacology; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism
chemical_list: D007473:Ion Channels; D019837:Ryanodine Receptor Calcium Release Channel; D009249:NADP; C024376:NAADP; D002118:Calcium