西亚试剂：NAADP mobilizes calcium from acidic organelles through two-

发布时间：2025-08-14

NAADP mobilizes calcium from acidic organelles through two-pore channels

Peter J. Calcraft1,7, Margarida Ruas2,7, Zui Pan3,7, Xiaotong Cheng2, Abdelilah Arredouani2, Xuemei Hao4,5, Jisen Tang5, Katja Rietdorf2, Lydia Teboul6, Kai-Ting Chuang2, Peihui Lin3, Rui Xiao5, Chunbo Wang5, Yingmin Zhu5, Yakang Lin5, Christopher N. Wyatt1, John Parrington2, Jianjie Ma3, A. Mark Evans1, Antony Galione2 & Michael X. Zhu5

1 Centre for Integrative Physiology, College of Medicine and Veterinary Medicine, University of Edinburgh, Hugh Robson Building, Edinburgh EH8 9XD, Scotland, UK
2 Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK
3 Department of Physiology and Biophysics, UMDNJ-Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, New Jersey 08854, USA
4 College of Life Sciences, Peking University, Beijing 100871, China
5 Department of Neuroscience, Biochemistry, and Center for Molecular Neurobiology, The Ohio State University, 1060 Carmack Road, Columbus, Ohio 43210, USA
6 The Mary Lyon Centre, MRC Harwell, Oxfordshire OX11 0RD, UK
7 These authors contributed equally to this work.

Ca²⁺ mobilization from intracellular stores represents an important cell signalling process1 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 controversial1, 2, although evidence indicates that NAADP mobilizes Ca²⁺ from lysosome-related acidic compartments3, 4. 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.

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