Alternative titles; symbols
HGNC Approved Gene Symbol: TPCN1
Cytogenetic location: 12q24.13 Genomic coordinates (GRCh38): 12:113,221,464-113,298,585 (from NCBI)
Voltage-gated Ca(2+) and Na+ channels have 4 homologous domains, each containing 6 transmembrane segments, S1 to S6. TPCN1 is similar to these channels, but it has only 2 domains containing S1 to S6 (Ishibashi et al., 2000).
By sequencing clones obtained from a size-fractionated human brain cDNA library, Hirosawa et al. (1999) cloned TPCN1, which they designated KIAA1169. The deduced 775-amino acid protein, which may be N-terminally truncated, contains motifs associated with ion transport proteins. RT-PCR ELISA detected robust expression in all adult and fetal tissues and specific brain regions examined. Highest expression was in heart and kidney, and lowest expression was in spleen.
Ishibashi et al. (2000) cloned rat Tpcn1, which they called Tpc1. The deduced 819-amino acid protein has a calculated molecular mass of 94.6 kD. It contains 2 homologous domains, each of which has 6 transmembrane segments (S1 to S6) and a putative pore loop between S5 and S6. Northern blot analysis detected a 5-kb transcript expressed at highest levels in rat kidney, followed by liver, lung, and spleen. In rat kidney, Tpc1 was expressed at the apical membrane of medullary collecting ducts. By EST database analysis, Ishibashi et al. (2000) identified likely human and plant orthologs of Tpc1.
Calcraft et al. (2009) showed that 2-pore channels (TPCs) comprise a family of nicotinic acid adenine dinucleotide phosphate (NAADP) receptors, with human TPC1 and chicken TPC3 being expressed on endosomal membranes, and human TPC2 on lysosomal membranes when expressed in HEK293 cells. Membranes enriched with TPC2 show high affinity NAADP binding, and TPC2 underpins NAADP-induced Ca(2+) release from lysosome-related stores that is subsequently amplified by Ca(2+)-induced Ca(2+) release by inositol-1,4,5-trisphosphate receptors (InsP3Rs). Responses to NAADP were abolished by disrupting the lysosomal proton gradient and by ablating TPC2 expression, but were only attenuated by depleting endoplasmic reticulum Ca(2+) stores or by blocking InsP3Rs. Thus, TPCs form NAADP receptors that release Ca(2+) from acidic organelles, which can trigger further Ca(2+) signals via sarcoplasmic/endoplasmic reticulum. Calcraft et al. (2009) concluded that TPCs provide insights into the regulation and organization of Ca(2+) signals in animal cells.
The International Radiation Hybrid Mapping Consortium mapped the TPCN1 gene to chromosome 12 (D12S1195E).
Calcraft, P. J., Ruas, M., Pan, Z., Cheng, X., Arredouani, A., Hao, X., Tang, J., Rietdorf, K., Teboul, L., Chuang, K.-T., Lin, P., Xiao, R., and 9 others. NAADP mobilizes calcium from acidic organelles through two-pore channels. Nature 459: 596-600, 2009. [PubMed: 19387438] [Full Text: https://doi.org/10.1038/nature08030]
Hirosawa, M., Nagase, T., Ishikawa, K., Kikuno, R., Nomura, N., Ohara, O. Characterization of cDNA clones selected by the GeneMark analysis from size-fractionated cDNA libraries from human brain. DNA Res. 6: 329-336, 1999. [PubMed: 10574461] [Full Text: https://doi.org/10.1093/dnares/6.5.329]
Ishibashi, K., Suzuki, M., Imai, M. Molecular cloning of a novel form (two-repeat) protein related to voltage-gated sodium and calcium channels. Biochem. Biophys. Res. Commun. 270: 370-376, 2000. [PubMed: 10753632] [Full Text: https://doi.org/10.1006/bbrc.2000.2435]