NAADP mobilizes calcium from acidic organelles through two-pore channels

By P. Calcraft, M. Ruas, Zui Pan, Xiaotong Cheng, A. Arredouani, Xuemei Hao, Jisen Tang, K. Rietdorf, L. Teboul, Kai-Ting Chuang and 11 more. Nature, 2009

763 citations recorded by the source corpus.

Ca2+ mobilization from intracellular stores represents an important cell signalling process that is regulated, in mammalian cells, by inositol-1,4,5-trisphosphate (InsP3), cyclic ADP ribose and nicotinic acid adenine dinucleotide phosphate (NAADP). InsP3 and cyclic ADP ribose cause the release of Ca2+ from sarcoplasmic/endoplasmic reticulum stores by the activation of InsP3 and ryanodine receptors (InsP3Rs and RyRs). In contrast, the nature of the intracellular stores targeted by NAADP and the molecular identity of the NAADP receptors remain controversial, although evidence indicates that NAADP mobilizes Ca2+ from lysosome-related acidic compartments. Here we show that two-pore channels (TPCs) comprise a family of NAADP receptors, with human TPC1 (also known as TPCN1) and chicken TPC3 (TPCN3) being expressed on endosomal membranes, and human TPC2 (TPCN2) on lysosomal membranes when expressed in HEK293 cells. Membranes enriched with TPC2 show high affinity NAADP binding, and TPC2 underpins NAADP-induced Ca2+ release from lysosome-related stores that is subsequently amplified by Ca2+-induced Ca2+ release by InsP3Rs. Responses to NAADP were abolished by disrupting the lysosomal proton gradient and by ablating TPC2 expression, but were only attenuated by depleting endoplasmic reticulum Ca2+ stores or by blocking InsP3Rs. Thus, TPCs form NAADP receptors that release Ca2+ from acidic organelles, which can trigger further Ca2+ signals via sarcoplasmic/endoplasmic reticulum. TPCs therefore provide new insights into the regulation and organization of Ca2+ signals in animal cells, and will advance our understanding of the physiological role of NAADP.

Subfields: Pharmacology, Physiology, Sensory Systems

View Paper: https://www.semanticscholar.org/paper/02bff2f3b7091252a7b50c6f58f27941e11a81fd

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In Physiology

1. Anjana Rao
2. P. Hogan
3. R. Lewis
4. S. Hawley
5. Fiona A. Ross
6. Dejian Ren
7. Haoxing Xu
8. D. Hardie

In Sensory Systems

1. R. Lewis
2. Anjana Rao
3. P. Hogan

Citations in the corpus

• Molecular Basis of Calcium Signaling in Lymphocytes: STIM and ORAI (2010, background): “Recent evidence indicates that in some cells NAADP releases Ca2+ from acidic stores such as lysosomes, endosomes, or melanosomes through twin-pore channels (TPCs) (51, 52).”
• Physiology of Astroglia. (2018, neutral): “The first two types of intracellular channels dwell in the endomembrane of the endoplasmic reticulum and mediate Ca(2) mobilization from the latter (1805), whereas TPCs are localized to the acidic Ca(2) stores (278).”
• Use of Cells Expressing γ Subunit Variants to Identify Diverse Mechanisms of AMPK Activation (2010, methodology): “Cytoplasmic Ca concentration was then reported by the Fura-2 fluorescence ratio (F340/F380 excitation; emission 510 nm) as previously described (Calcraft et al., 2009).”
• Lysosomal Physiology (2015, background): “TPCs were first functionally characterized as candidates for NAADP-activated Ca2+release channels (110).”