In Focus: Two Pore Segment Channels (TPCs)

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 rodents⁹. 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) channels⁶. These twelve transmembrane structures are further thought to form functional dimers⁵. Both TPC1 and TPC2 show ubiquitous expression, while that of TPC1 is exceptionally high in spleen, lung, liver, and kidney⁶.

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 concentration¹. 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)^4,7. 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+ 2,3}. 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 increases and exacerbates Ca²⁺ release respectively². In addition, b-cells from TPC2 knockout mice exhibited no Ca²⁺ release from endolysosomes upon NAADP stimulation³. 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+ 8}.

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 deciphered⁹.

Alomone Labs is pleased to offer highly specific antibodies against TPC1 and TPC2. Anti-TPCN1 Antibody (#ACC-071) and Anti-TPCN2 Antibody (#ACC-072) can be used in western blot analysis and/or immunohistochemistry.

References

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