Essential requirement for two-pore channel 1 in NAADP-mediated calcium signaling.
Nicotinic acid adenine dinucleotide phosphate (NAADP) is a widespread and potent calcium-mobilizing messenger that is highly unusual in activating calcium channels located on acidic stores. However, the molecular identity of the target protein is unclear. In this study, we show that the previously uncharacterized human two-pore channels (TPC1 and TPC2) are endolysosomal proteins, that NAADP-mediated calcium signals are enhanced by overexpression of TPC1 and attenuated after knockdown of TPC1, and that mutation of a single highly conserved residue within a putative pore region abrogated calcium release by NAADP. Thus, TPC1 is critical for NAADP action and is likely the long sought after target channel for NAADP.
Brailoiu
Eugen
E
Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Churamani
Dev
D
Cai
Xinjiang
X
Schrlau
Michael G
MG
Brailoiu
G Cristina
GC
Gao
Xin
X
Hooper
Robert
R
Boulware
Michael J
MJ
Dun
Nae J
NJ
Marchant
Jonathan S
JS
Patel
Sandip
S
D000595:Amino Acid Sequence; D000818:Animals; D015220:Calcium Channels / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D002478:Cells, Cultured; D011992:Endosomes / Q000378:metabolism*; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation; D009249:NADP / Q000031:analogs & derivatives* / Q000378:metabolism; D010802:Phylogeny; D016415:Sequence Alignment; D000097903:Two-Pore Channels
D015220:Calcium Channels; D009249:NADP; C407357:TPCN1 protein, human; D000097903:Two-Pore Channels; C530224:TPCN2 protein, human; C024376:NAADP