Spatial control of Ca2+ signaling by nicotinic acid adenine dinucleotide phosphate diffusion and gradients

Intracellular Ca2+ is able to control numerous cellular responses through complex spatiotemporal organization. Ca2+ waves mediated by inositol trisphosphate or ryanodine receptors propagate by Ca2+-induced Ca2+ release and therefore do not have an absolute requirement for a gradient in either inositol trisphosphate or cyclic ADP-ribose, respectively. In contrast, we report that although Ca2+ increases induced by nicotinic acid adenine dinucleotide phosphate (NAADP) are amplified by Ca2+-induced Ca2+ release locally, Ca2+ waves mediated by NAADP have an absolute requirement for an NAADP gradient. If NAADP is increased such that its concentration is spatially uniform in one region of an egg, the Ca2+ increase occurs simultaneously throughout this area, and only where there is diffusion out of this area to establish an NAADP gradient is there a Ca2+ wave. A local increase in NAADP results in a Ca2+ increase that spreads by NAADP diffusion. NAADP diffusion is restricted at low but not high concentrations of NAADP, indicating that NAADP diffusion is strongly influenced by binding to immobile and saturable sites, probably the NAADP receptor itself. Thus, the range of action of NAADP can be tuned by its concentration from that of a local messenger, like Ca2+, to that of a global messenger, like IP3 or cyclic ADP-ribose.