title: Convergent regulation of the lysosomal two-pore channel-2 by Mg²⁺, NAADP, PI(3,5)P₂ and multiple protein kinases.
abstract: Lysosomal Ca(2+) homeostasis is implicated in disease and controls many lysosomal functions. A key in understanding lysosomal Ca(2+) 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)P2 activated channels regulated by mTORC1, but not by NAADP. Here, we identified Mg(2+) and the MAPKs, JNK and P38 as novel regulators of TPC2. Cytoplasmic Mg(2+) specifically inhibited TPC2 outward current, whereas lysosomal Mg(2+) partially inhibited both outward and inward currents in a lysosomal lumen pH-dependent manner. Under controlled Mg(2+), TPC2 is readily activated by NAADP with channel properties identical to those in response to PI(3,5)P2. Moreover, TPC2 is robustly regulated by P38 and JNK. Notably, NAADP-mediated Ca(2+) release in intact cells is regulated by Mg(2+), PI(3,5)P2, and P38/JNK kinases, thus paralleling regulation of TPC2 currents. Our data affirm a key role for TPC2 in NAADP-mediated Ca(2+) signaling and link this pathway to Mg(2+) homeostasis and MAP kinases, pointing to roles for lysosomal Ca(2+) in cell growth, inflammation and cancer.
authors: Epithelial Signaling and Transport Section, Molecular Physiology and Therapeutics Branch, NIDCR NIH, Bethesda, MD, USA.
authors: Archana
authors: A
authors: Jha
authors: Malini
authors: M
authors: Ahuja
authors: Sandip
authors: S
authors: Patel
authors: Eugen
authors: E
authors: Brailoiu
authors: Shmuel
authors: S
authors: Muallem
mesh_terms: D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism*; D002413:Cations, Divalent / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006706:Homeostasis; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D008274:Magnesium / Q000378:metabolism*; D009249:NADP / Q000031:analogs & derivatives* / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D015220:Calcium Channels; D002413:Cations, Divalent; D010716:Phosphatidylinositols; C530224:TPCN2 protein, human; D009249:NADP; C024376:NAADP; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D008274:Magnesium; D002118:Calcium