Researchers had already identified a molecular key that opens some intracellular calcium storehouses. Brailoiu et al. now reveal the door, the channel that actually lets calcium exit.
Cells stow calcium within certain organelles, releasing it into the cytosol in response to myriad cues. Researchers have pinpointed the messengers that spur the endoplasmic reticulum (ER) to unload its calcium. Another signal, NAADP, triggers so-called acidic stores—the endosomes and lysosomes—to do the same, but which calcium channel NAADP activates was uncertain. A recent study revealed that in plants, the two-pore channels release calcium from the vacuole, another acidic environment. Brailoiu et al. wondered whether NAADP might target one of these little-known channels in animals.
The channels are in the right place; in cells engineered to produce human two-pore channels, the molecules were expressed in the endosomes and lysosomes, but not the ER. The channels' abundance dictates responsiveness to NAADP. When human cells fashioned extra amounts of the channel TPC1, they were hypersensitive to NAADP. But when the researchers reduced TPC1 levels by RNAi, the cells discharged little calcium after stimulation. What's more, mutation of a single, conserved amino acid in the putative pore region of TPC1 prevented NAADP-induced calcium release.
The work suggests that TPC1 is a target of NAADP, complementing a Nature paper published in May that showed NAADP spurs calcium release via TPC2. Researchers now need to work out whether NAADP acts directly on the channels or through intermediaries.