Nicotinic acid dinucleotide phosphate (NAADP) is unique amongst Ca(2+) mobilizing messengers in that its principal function is to mobilize Ca(2+) from acidic organelles. Early studies indicated that it was likely that NAADP activates a novel Ca(2+) release channel distinct from the well characterized Ca(2+) release channels on the (sarco)-endoplasmic reticulum (ER), inositol trisphosphate and ryanodine receptors. In this review, we discuss the emergence of a novel family of endolysosomal channels, the two-pore channels (TPCs), as likely targets for NAADP, and how molecular and pharmacological manipulation of these channels is enhancing our understanding of the physiological roles of NAADP as an intracellular Ca(2+) mobilizing messenger.
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