Nicotinic acid adenine dinucleotide phosphate (NAADP) mobilizes Ca(2+) in many cells and species. Unlike other Ca(2+)-mobilizing messengers, NAADP mobilizes Ca(2+) from an unknown store that is not the endoplasmic reticulum, the store traditionally associated with messenger-mediated Ca(2+) signaling. Here, we demonstrate the presence of a Ca(2+) store in sea urchin eggs mobilized by NAADP that is dependent on a proton gradient maintained by an ATP-dependent vacuolar-type proton pump. Moreover, we provide pharmacological and biochemical evidence that this Ca(2+) store is the reserve granule, the functional equivalent of a lysosome in the sea urchin egg. These findings represent an unsuspected mechanism for messenger-mediated Ca(2+) release from lysosome-related organelles.

Recent work on consumption allocations in village economies finds that idiosyncratic variation in consumption is systematically related to idiosyncratic variation in income, thus rejecting the hypothesis of full risk-pooling. We attempt to explain these observations by adding limited commitment as an impediment to risk-pooling. We provide a general dynamic model and completely characterise efficient informal insurance arrangements constrained by limited commitment, and test the model using data from three Indian villages. We find that the model can fully explain the dynamic response of consumption to income, but that it fails to explain the distribution of consumption across households. (2002) 69, 209-244 0034-6527/02/00090209$02.00 ß 2002 The Review of Economic Studies Limited 209 2. Examples include applications to sovereign debt by Kletzer and Wright (2000) and Atkeson (1991) (who also considers asymmetric information), Chari and Kehoe (1993) who consider a model in which both the government and private citizens can default on their debt to each other, a two-country international business cycle model with both production and capital accumulation by Kehoe and Perri (1998), a two-party model of political bargaining by Dixit, Grossman and Gul (1998) and a model of asset pricing by Alvarez and Jermann (2000). Review of Economic Studies3. Alvarez and Jermann (2000) obtain a similar characterization to that here in a two-sided risk aversion case but assume symmetry, no aggregate uncertainty and a monotonicity property.

Research into the biological role of the Ca2+-releasing second messenger NAADP (nicotinic acid adenine dinucleotide phosphate) has been hampered by a lack of chemical probes. To find new chemical probes for exploring NAADP signaling, we turned to virtual screening, which can evaluate millions of molecules rapidly and inexpensively. We used NAADP as the query ligand to screen the chemical library ZINC for compounds with 3D-shape and electrostatic similarity. We tested the top-ranking hits in a sea urchin egg bioassay and found that one hit, Ned-19, blocks NAADP signaling at nanomolar concentrations. In intact cells, Ned-19 blocked NAADP signaling and fluorescently labeled NAADP receptors. Moreover, we show the utility of Ned-19 as a chemical probe by using it to demonstrate that NAADP is a key causal link between glucose sensing and Ca2+ increases in mouse pancreatic beta cells.

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