期刊
NATURE
卷 459, 期 7246, 页码 596-U130出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nature08030
关键词
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资金
- UK Wellcome Trust [070772]
- British Heart Foundation
- US National Institutes of Health
- American Heart Association
- British Heart Foundation [FS/05/050]
- US National Institutes of Health [P30-NS045758]
- Medical Research Council [MC_UP_1502/1] Funding Source: researchfish
- MRC [MC_UP_1502/1] Funding Source: UKRI
Ca2+ mobilization from intracellular stores represents an important cell signalling process(1) that is regulated, in mammalian cells, by inositol-1,4,5-trisphosphate (InsP(3)), cyclic ADP ribose and nicotinic acid adenine dinucleotide phosphate (NAADP). InsP(3) and cyclic ADP ribose cause the release of Ca2+ from sarcoplasmic/endoplasmic reticulum stores by the activation of InsP(3) and ryanodine receptors (InsP(3)Rs and RyRs). In contrast, the nature of the intracellular stores targeted by NAADP and the molecular identity of the NAADP receptors remain controversial(1,2), although evidence indicates that NAADP mobilizes Ca2+ from lysosome-related acidic compartments(3,4). 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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