Interactions between calcium release pathways: multiple messengers and multiple stores

The discovery of cyclic adenosine diphosphate ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP) as Ca2+ releasing messengers has provided additional insight into how complex Ca2+ signalling patterns are generated. There is mounting evidence that these molecules along with the more established messenger, myo-inositol 1,4,5-trisphosphate (IP3), have a widespread messenger role in shaping Ca2+ signals in many cell types. These molecules have distinct structures and act on specific Ca2+ release mechanisms. Emerging principles are that cADPR enhances the Ca2+ sensitivity of ryanodine receptors (RYRs) to produce prolonged Ca2+ signals through Ca2+-induced Ca2+ release (CICR), while NAADP acts on a novel Ca2+ release mechanism to produce a local trigger Ca2+ signal which can be amplified by CICR by recruiting other Ca2+ release mechanisms. Whilst IP3 and cADPR mobilis(e) Ca2+ from the endoplasmic reticulum (ER), recent evidence from the sea urchin egg suggests that the major NAADP-sensitive Ca2+ stores are reserve granules, acidic lysosomal-related organelles. In this review we summarise the role of multiple Ca2+ mobilising messengers, Ca2+ release channels and Ca2+ stores, and the interplay between them, in the generation of specific Ca2+ signals. Focusing upon cADPR and NAADP, we discuss how cellular stimuli may draw upon different combinations of these messengers to produce distinct Ca2+ signalling signatures. (C) 2002 Elsevier Science Ltd. All rights reserved.