TPC proteins are phosphoinositide- activated sodium-selective ion channels in endosomes and lysosomes.
Mammalian two-pore channel proteins (TPC1, TPC2; TPCN1, TPCN2) encode ion channels in intracellular endosomes and lysosomes and were proposed to mediate endolysosomal calcium release triggered by the second messenger, nicotinic acid adenine dinucleotide phosphate (NAADP). By directly recording TPCs in endolysosomes from wild-type and TPC double-knockout mice, here we show that, in contrast to previous conclusions, TPCs are in fact sodium-selective channels activated by PI(3,5)P(2) and are not activated by NAADP. Moreover, the primary endolysosomal ion is Na(+), not K(+), as had been previously assumed. These findings suggest that the organellar membrane potential may undergo large regulatory changes and may explain the specificity of PI(3,5)P(2) in regulating the fusogenic potential of intracellular organelles.
Department of Molecular, Cellular, and Developmental Biology, University of Michigan, 3089 Kraus Natural Science Building, 830 North University Avenue, Ann Arbor, MI 48109, USA.
Xiang
X
Wang
Xiaoli
X
Zhang
Xian-Ping
XP
Dong
Mohammad
M
Samie
Xinran
X
Li
Xiping
X
Cheng
Andrew
A
Goschka
Dongbiao
D
Shen
Yandong
Y
Zhou
Janice
J
Harlow
Michael X
MX
Zhu
David E
DE
Clapham
Dejian
D
Ren
Haoxing
H
Xu
D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D005947:Glucose / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009249:NADP / Q000031:analogs & derivatives / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D015222:Sodium Channels / Q000378:metabolism; D000097903:Two-Pore Channels
D002118:Calcium; D015220:Calcium Channels; D005947:Glucose; D009249:NADP; D018129:Phosphatidylinositol Phosphates; D015222:Sodium Channels; C546784:TPCN1 protein, mouse; D000097903:Two-Pore Channels; C546785:TPCN2 protein, mouse; C024376:NAADP