Synthesis and biological testing of cell-permeant NAADP

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Cells communicate with other cells and internally via chemical messengers. These messenger are molecules and exhibit features that make them uniquely recognizable to specialised receptors, or biological message centres. Messengers are made inside the cell membrane in response to outside stimuli, but cannot cross to or from the outside. This is because cells are enveloped by a membrane which keeps the contents in and potential contaminants outside. We are interested in a messenger molecule that increases calcium levels inside cells, called NAADP. Changes in calcium levels is what drives your heart to contract, your arm muscle to contract to raise a cup to your mouth and even the cells in your brain to talk to each other. Nobody is yet sure NAADP is working, so we want to get it into cells and find out. This messenger molecule does not naturally cross the cell membrane, so current state of the art techniques involve destroying the membrane then rebuilding it. This is difficult and requires specialised skills. We propose to try a different, more subtle approach by masking the molecules appearance, so that it can slip through the membrane. Once inside, the molecule sheds its mask, regains its appearance and provides its message. Getting NAADP across the cell membrane by stealth will provide us with new information about how this messenger works in different cells. Successful development of this new method will allow many more scientists to study this fascinating molecule.