Title : The two-pore
channel TPCN2 mediates NAADP-dependent
Ca( 2+)-release from lysosomal stores
Abstract :
- Second messenger-induced Ca( 2+)-release from intracellular stores plays a key role in a multitude of physiological processes
- In addition to 1,4,5-inositol trisphosphate (IP(3)), Ca( 2+), and cyclic ADP ribose (cADPR) that trigger Ca( 2+)-release from the endoplasmatic reticulum (ER), nicotinic acid adenine dinucleotide phosphate (NAADP) has been identified as a cellular metabolite that mediates Ca( 2+)-release from lysosomal stores
- While NAADP-induced Ca( 2+)-release has been found in many tissues and cell types, the molecular identity of the channel (s) conferring this release remained elusive so far
- Here, we show that TPCN2 , a novel member of the two-pore cation channel family, displays the basic properties of native NAADP-dependent Ca( 2+)-release channels
- TPCN2 transcripts are widely expressed in the body and encode a lysosomal protein forming homomers
- TPCN2 mediates intracellular Ca( 2+)-release after activation with low-nanomolar concentrations of NAADP while it is desensitized by micromolar concentrations of this second messenger and is insensitive to the NAADP analog nicotinamide adenine dinucleotide phosphate (NADP)
- Furthermore, TPCN2-mediated Ca(2 +)-release is almost completely abolished when the capacity of lysosomes for storing Ca( 2+) is pharmacologically blocked
- By contrast, TPCN2-specific Ca(2 +)-release is unaffected by emptying ER-based Ca( 2+) stores
- In conclusion, these findings indicate that TPCN2 is a major component of the long-sought lysosomal NAADP-dependent Ca( 2+)-release channel
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