naadp

Ca2+ mobilizing agent

Nicotinic acid adenine dinucleotide phosphate (NAADP) is a secondary messenger that induces calcium mobilization. It induces calcium release from endosomes and lysosomes via two-pore channel 2 (TPC2) and TPC1, which then stimulates large-scale calcium release from granules and the endoplasmic reticulum mediated by type 1 ryanodine receptors (RyR2s), RyR3s, and inositol-(1,4,5)-triphosphate receptors (IP3Rs). NAADP induces calcium mobilization in sea urchin and starfish eggs post fertilization to block polyspermy and activate embryogenesis. NAADP-induced calcium mobilization induces VEGF-mediated angiogenesis in human umbilical vein endothelial cells (HUVECs). It also alkalizes lysosomal pH thereby inhibiting fusion between autophagosomes and lysosomes and arresting autophagic flux in mouse embryonic stem cells.

Ned 19 is a selective membrane-permeant non competitive antagonist of NAADP and strongly inhibits tumor growth and vascularization as well as lung metastases in mice.

trans-Ned 19 is a NAADP antagonist and TPC blocker and inhibits the calcium signal in human umbilical vein endothelial cells and the rat aorta relaxation in response to low histamine concentrations.

nicotinic acid adenine dinucleotide phosphate (NAADP) antagonist

Ned-K is a nicotinic acid adenine dinucleotide phosphate (NAADP) antagonist that exhibits an inhibitory effect on myocardial ischemia and reperfusion (sIR)-induced calcium oscillations.

TPC2-A1-N is a novel, lipophilic, membrane permeable isoform-selective small molecule agonist of two-pore channel 2 (TPC2). TPC2-A1-N plays its role by mimicking the physiological actions of NAADP and PI(3,5)P2 through independent binding sites. TPC2-A1-N has inverse effects on key lysosomal activities and increases the pH in the lysosomal lumen in a TPC2-dependent manner[1]. Two-pore channels (TPC1-3) are ancient members of the voltage-gated ion channel superfamily. TPCs are expressed throughout the endo-lysosomal system and regulates the trafficking of various cargoes.TPC2 can mediate different physiological and possibly pathophysiological effects depending on how it is activated. The ion selectivity of TPC2 is not fixed but rather agonist-dependent. TPC2 is a unique example of an ion channel that conducts different ions in response to different activating ligands.TPC2-A1-N (10 μM) reproducibly evokes Ca2+ signals, and TPC2-A1-N response reachs its plateau faster than TPC2-A1-P. The EC50 in full concentration-effect relationships for the plateau response is 7.8 μM for TPC2-A1-N in a cell line stably expressing TPC2L11A/L12A.TPC2-A1-N (10 μM) evokes Ca2+ influx through the TPC2 pore evokes Ca2+ signals in cells expressing TPC2L11A/L12A but not TPC2L11A/L12A/L265P. Additionally, the responses to TPC2-A1-N can be selectively blocked by the identified TPC2 blockers Tetrandrine , Raloxifene , and Fluphenazine by removal of extracellular Ca2+[1].In endo-lysosomal patch-clamp experiments, TPC2-A1-N (30 μM) elicits currents using Na+ as the major permeant ion, in vacuolin-enlarged endo-lysosomes isolated from isolated from HEK293 cells transiently expressing human TPC2 (hTPC2) but not in cells expressing TPC1[1].In endo-lysosomal patch-clamp experiments, TPC2-A1-N (30 μM) induces larger currents in endo-lysosomes isolated from cells expressing a gain-of-function variant of TPC2 (TPC2M484L) compared to the wild-type isoform, and exhibits an EC50 value of 0.6 μM for TPC2-A1-N[1]. [1]. Susanne Gerndt, et al. Agonist-mediated switching of ion selectivity in TPC2 differentially promotes lysosomal function. Elife