NAADP as an intracellular messenger regulating lysosomal calcium-release channels

Abstract

Recent studies into the mechanisms of action of the Ca(2+)-mobilizing messenger NAADP (nicotinic acid-adenine dinucleotide phosphate) have demonstrated that a novel family of intracellular Ca(2+)-release channels termed TPCs (two-pore channels) are components of the NAADP receptor. TPCs appear to be exclusively localized to the endolysosomal system. These findings confirm previous pharmacological and biochemical studies suggesting that NAADP targets acidic Ca(2+) stores rather than the endoplasmic reticulum, the major site of action of the other two principal Ca(2+)-mobilizing messengers, InsP(3) and cADPR (cADP-ribose). Studies of the messenger roles of NAADP and the function of TPCs highlight the novel role of lysosomes and other organelles of the endocytic pathway as messenger-regulated Ca(2+) stores which also affects the regulation of the endolysosomal system.

Identification of Two-pore Channel 2 as a Novel Regulator of Osteoclastogenesis

“…We assume that the calcium-calcineurin pathway may be affected in TPC2-knockdown cells. (8,12,13,28). We showed the role of TPC2 in osteoclasts.…”

“…To address roles of TPC2 action in regulation of signaling associated with osteoclast differentiation, we examined the effects of TPC2 knockdown on nuclear localization of NFATc1 because TPC2 regulates [Ca 2ϩ ] i (12,13) that is critical for osteoclastogenesis based on nuclear translocation of NFATc1. To this end, subcellular localization of NFATc1 was examined using an antibody against NFATc1 after RANKL treatment.…”

“…NAADP evokes Ca 2ϩ release via TPC2. This often leads to recruitment of further Ca 2ϩ release from the ER through IP 3 Rs or ryanodine receptors (12,13). TPC2 is required for myocyte differentiation (14,15).…”

“…TPC2 is a specific lysosomal calcium channel that does not localize in endosome, ER, Golgi, and mitochondria (12). Two isoforms, TPC1 and TPC2, have been cloned as translation products of different genes in mammals, and TPC1 localizes predominantly in endosomes (12,13). NAADP evokes Ca 2ϩ release via TPC2.…”

NAADP-sensitive Сa(2+) stores in permeabilized rat hepatocytes

“…N icotinic acid adenine dinucleotide phosphate (NAADP) is a naturally occurring nucleotide that has been shown to be involved in calcium release from intracellular stores in a wide variety of cell types [1]. The first demonstration that NAADP levels increase in response to an extracellular stimulus arose from studying sea urchin fertilization (NAADP changed in both the eggs and sperm upon contact) [2].…”