Among various vertebrate species, three genes are known to encode two-pore segment channels (TPCs) termed TPC1-3. Interestingly TPC3 seems to be absent from the genomes of primates and rodents¹. The primary sequence of these channels indicates the presence of two putative pore-forming repeats. Each repeat contains six transmembrane domains and a pore loop, a structure strikingly reminiscent of many voltage-gated Na⁺ (Na_V) and Ca²⁺ (Ca_V) channels². These twelve transmembrane structures are further thought to form functional dimers³. Both TPC1 and TPC2 show ubiquitous expression, while that of TPC1 is exceptionally high in spleen, lung, liver, and kidney².

Ca²⁺-mobilizing messengers such as inositol triphosphate, cyclic ADP ribose and nicotinic acid adenosine dinucleotide phosphate (NAADP) are responsible for the intracellular changes in Ca²⁺ ion concentration⁴.

In contrast to the other Ca²⁺-mobilizing agents, NAADP, the most potent of these Ca²⁺ releasing molecules increases the cytosolic Ca²⁺ concentration via Ca²⁺ channels located on acidic vesicles (endolysosomes)^5,6. Only quite recently, after almost a decade of being cloned, TPC1 and TPC2 were both found to be responsible for the NAADP-induced release of Ca^2+ 7,8. Evidence that these two channels are indeed responsible for the release of Ca²⁺ is quite compelling since overexpression of TPC1 and its knockdown or point mutation of a critical residue increase and exacerbate Ca²⁺ release respectively⁷. In addition, b-cells from TPC2 knockout mice exhibited no Ca²⁺ release from endolysosomes upon NAADP stimulation⁸. Finally, in a study using immunopurified channels, it was demonstrated that TPC1 and TPC2 both respond to very low concentrations of NAADP and are unequivocally responsible for the release of Ca²⁺, whereas TPC3 may negatively regulate the release of Ca^2+ 9.

As these channels have only recently been discovered, very little is known about their physiology and gating mechanisms. Their probable involvement in a number of diseases such as lysosomal storage disease (LSDs), caused by the dysfunction of lysosomal associated proteins, has yet to be deciphered¹.