Adv Exp Med Biol 2012 Jan 01;740:325-47. doi: 10.1007/978-94-007-2888-2_14.

NAADP on target.

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Nicotinic acid adenine dinucleotide phosphate (NAADP) is a potent intracellular Ca(2+)-mobilising messenger. Much evidence indicates that NAADP targets novel Ca(2+) channels located on acidic organelles but the identity of these channels has remained obscure. Recent studies have converged on a novel class of ion channels, the two-pore channels (TPCs) as likely molecular targets. The location of these channels to the endo-lysosomal system and their sensitivity to NAADP match closely those of endogenous NAADP-sensitive channels in both mammalian cells and sea urchin eggs, where the effects of NAADP were discovered. Moreover, the functional coupling of TPCs to archetypal endoplasmic reticulum (ER) Ca(2+) channels is also matched. Biophysical analysis in conjunction with site-directed mutagenesis demonstrates that TPCs are pore-forming subunits of NAADP-gated ion channels. TPCs have a unique two-repeat structure, are regulated by N-linked glycosylation and harbor an endo-lysosomal targeting motif in their N-terminus. Knockdown studies have shown TPCs to regulate smooth muscle contraction, differentiation and endothelial cell activation consistent with previous studies implicating NAADP in these processes. Thus multiple lines of evidence indicate that TPCs are the likely long sought targets for NAADP.

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Genes referenced: LOC100887844 LOC100893907 LOC115919910 LOC115925116 LOC576539