Journal
EMBO JOURNAL
Volume 33, Issue 5, Pages 501-511Publisher
WILEY
DOI: 10.1002/embj.201387035
Keywords
channel; lysosome; Mg2+; NAADP; TPC2
Categories
Funding
- National Institutes of Health [HL090804]
- NIH/NIDCR [DE000735-03]
- BBSRC [BB/G013721/1, BB/K000942/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/K000942/1, BB/G013721/1] Funding Source: researchfish
Ask authors/readers for more resources
Lysosomal Ca2+ homeostasis is implicated in disease and controls many lysosomal functions. A key in understanding lysosomal Ca2+ signaling was the discovery of the two-pore channels (TPCs) and their potential activation by NAADP. Recent work concluded that the TPCs function as a PI(3,5)P-2 activated channels regulated by mTORC1, but not by NAADP. Here, we identified Mg2+ and the MAPKs, JNK and P38 as novel regulators of TPC2. Cytoplasmic Mg2+ specifically inhibited TPC2 outward current, whereas lysosomal Mg2+ partially inhibited both outward and inward currents in a lysosomal lumen pH-dependent manner. Under controlled Mg2+, TPC2 is readily activated by NAADP with channel properties identical to those in response to PI(3,5)P-2. Moreover, TPC2 is robustly regulated by P38 and JNK. Notably, NAADP-mediated Ca2+ release in intact cells is regulated by Mg2+, PI(3,5)P-2, and P38/JNK kinases, thus paralleling regulation of TPC2 currents. Our data affirm a key role for TPC2 in NAADP-mediated Ca2+ signaling and link this pathway to Mg2+ homeostasis and MAP kinases, pointing to roles for lysosomal Ca2+ in cell growth, inflammation and cancer.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available