. NAADP mobilizes calcium from acidic organelles through two-pore channels. Nature. 2009 May 28;459(7246):596-600. PubMed.

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  1. It is well established that most of intracellular Ca2+ is stored in the endoplasmic reticulum (ER) and that stored Ca2+ can be released by activation of InsP3-gated InsP3R channels or Ca2+-gated RyanR channels in the ER. The potential importance of excessive Ca2+ release via InsP3R and RyanR channels in neuronal aging and AD pathology has been extensively discussed (1,2). In addition to InsP3-sensitive and Ca2+-sensitive intracellular Ca2+ pools, it has been demonstrated that a distinct pool of intracellular Ca2+ can be released by nicotinic acid adenine dinucleotide phosphate (NAADP). The initial discovery of an NAADP-sensitive Ca2+ pool was made in experiments with homogenates from sea urchin eggs almost 15 years ago (3), but the exact nature of the NAADP-gated channel and the corresponding Ca2+ pool remained a mystery. In 2002, again in experiments with sea urchin egg homogenates, it was demonstrated that the NAADP-sensitive Ca2+ pool appears to be localized to lysosomal organelles (4). By following this lead, the authors of the present paper report that a novel two-pore channel, TPC2, appears to form the NAADP-sensitive Ca2+ channel.

    The evidence supporting this idea is as follows: 1) TPC2 channels are abundant in lysosomal compartments; 2) NAADP binding sites are increased in TPC2 stably transfected cells; 3) TPC2-transfected cells are sensitized to NAADP-induced Ca2+ release; 4) and most importantly, pancreatic β cells from TPC2 knockout mice lose NAADP-induced responses. This is quite strong evidence supporting the role of TPC2 in forming the NAADP-gated Ca2+ channels. It is, however, still unclear if additional subunits are required to make such channels and if NAADP binds to TPC2 directly.

    What is the relevance of these findings to Alzheimer disease? The TPC2 channel appears to be mainly expressed in kidney and liver, but it is possible that some neuronal populations express TPC2. This remains to be determined. TPC2 knockout mice are available), and it will be interesting to evaluate neuronal Ca2+ signaling in these mice. Also, these findings raise interesting questions about the function of the TPC1 homolog, which may also play a role in neuronal Ca2+ signaling. Overall, identification of the TPC family as potential NAADP-sensitive channels opens a door for studies of the role played by this additional Ca2+ pool in neuronal Ca2+ signaling and AD pathogenesis.

    References:

    . The pathogenesis of Alzheimers disease is it a lifelong "calciumopathy"?. Neuroscientist. 2007 Oct;13(5):546-59. PubMed.

    . Neuronal calcium mishandling and the pathogenesis of Alzheimer's disease. Trends Neurosci. 2008 Sep;31(9):454-63. PubMed.

    . A derivative of NADP mobilizes calcium stores insensitive to inositol trisphosphate and cyclic ADP-ribose. J Biol Chem. 1995 Feb 3;270(5):2152-7. PubMed.

    . NAADP mobilizes Ca(2+) from reserve granules, lysosome-related organelles, in sea urchin eggs. Cell. 2002 Nov 27;111(5):703-8. PubMed.