Abstract
Nicotinic acid adenine dinucleotide phosphate (NAADP) is a potent Ca(2+)-mobilizing agent in invertebrate eggs that has recently been shown to be active in certain mammalian and plant systems. Little, however, is known concerning the properties of putative NAADP receptors. Here, for the first time, we report binding sites for NAADP in brain. In contrast to sea urchin egg homogenates, [(32)P]NAADP bound reversibly to multiple sites in brain membranes. The rank order of potency of NAADP, 2',3'-cyclic NAADP and 3'-NAADP in displacing [(32)P]NAADP was, however, the same in the two systems and in agreement with their ability to mobilize Ca(2+) from homogenates. These data indicate that [(32)P]NAADP likely binds to receptors mediating Ca(2+) mobilization. Autoradiography revealed striking heterogeneity in the distribution of [(32)P]NAADP binding sites throughout the brain. Our data strongly support a role for NAADP-induced Ca(2+) signaling in the brain.
Highlights
Nicotinic acid adenine dinucleotide phosphate (NAADP) is a potent Ca2؉-mobilizing agent in invertebrate eggs that has recently been shown to be active in certain mammalian and plant systems
NAADP releases Ca2ϩ from a pool distinct from that mobilized by IP3 and cyclic ADP-ribose (cADPR) [12, 15, 16], and NAADP-induced Ca2ϩ mobilization is not regulated by Ca2ϩ [16, 17], a property that underlies regenerative Ca2ϩ release via IP3 and ryanodine receptors [1, 2]
Binding of [32P]NAADP (1–2 nM) to the sections was performed for 2 h at 20 °C in a medium composed of 20 mM HEPES and 1 mM EDTA
Summary
In non-excitable cells, a variety of extracellular stimuli mediate changes in cytosolic [Ca2ϩ] through the mobilization of intracellular Ca2ϩ stores [3] This is achieved through the concerted activation of a family of related intracellular Ca2ϩ channels/receptor complexes for inositol 1,4,5-trisphosphate (IP3)1 [4, 5] and ryanodine [6]. A novel Ca2ϩ-mobilizing messenger, nicotinic acid adenine dinucleotide phosphate (NAADP) has been described in sea urchin eggs [7], which, based on cross-desensitization experiments [12] and distinct pharmacology [13], is thought to release Ca2ϩ independently of IP3 or ryanodine receptor activation. A binding site for NAADP has been previously demonstrated in sea urchin egg microsomes [14]; little is known concerning the molecular identity or distribution of putative NAADP receptors. Our data support a general role for NAADP-mediated Ca2ϩ signaling in the brain
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