TPCN2 Membrane Protein Introduction

Introduction of TPCN2

TPCN2 (two-pore calcium channel protein 2) is a human protein encoded by TPCN2 gene, which serves as a putative cation-selective ion channel with two repeated six-transmembrane-domain. The location of the TPCN2 is on lysosomal membranes, which enables nicotinic acid adenine dinucleotide phosphate (NAADP)-induced calcium ion release from lysosome-related stores.

Function of TPCN2 Membrane Protein

TPCN2 plays a significant role in cellular calcium ion homeostasis, ion transmembrane transport, lysosome organization and regulation of autophagy. As one of the NAADP receptors, TPCN2 functions as one of the major voltage-gated Ca²⁺ channels across the lysosomal membrane. TPCN2 could enhance the affinity of NAADP binding to membranes, and increase NAADP-induced Ca²⁺ release from lysosome-related stores which is subsequently amplified by Ca²⁺-induced Ca²⁺ release via inositol 1,4,5-trisphosphate. Similar to TPCN1, TPCN2 has been identified as a potential factor of reverse disease phenotypes, like diabetes, cancer, cardiac dysfunction, Parkinson's disease and so on.

Fig.1 A structural model of human TPC2. (Patel, 2018)

Application of TPCN2 Membrane Protein in Literature

1. Sun W. and Yue J. TPC2 mediates autophagy progression and extracellular vesicle secretion in cancer cells. Experimental Cell Research. 2018, 370(2): 478-489. PubMed ID: 29990474
   
   

   This article mainly researched the role of TPCN2 in autophagy progression. The results indicated that TPC overexpression inhibited the fusion between autophagosome and lysosome and resulted in accumulation of autophagosomes accompanied with increase of lysosomal pH and transcription factor EB nuclear localization. Also, TPC2 overexpression decreased secretion of extracellular vesicle.

2. Kelu J.J., et al. TPC2-mediated Ca²⁺ signaling is required for the establishment of synchronized activity in developing zebrafish primary motor neurons. Developmental Biology. 2017, 438(1): 57-68. PubMed ID: 29577882
   
   

   This study demonstrated that TPCN2 induced Ca²⁺ release from acidic stores or endolysosomes was necessary for the establishment of synchronized activity in the primary motor neurons. And Ca²⁺ signaling mediated by NAADP/TPC2 was important in the development and maturation of the spinal network in zebrafish embryos.

3. Kelu J.J., et al. Ca²⁺ release via two-pore channel type 2 (TPC2) is required for slow muscle cell myofibrillogenesis and myotomal patterning in intact zebrafish embryos. Developmental Biology. 2017, 425(2): 109-129. PubMed ID: 28390800
   
   

   The researchers confirmed that Ca²⁺ release induced by TPC2 might trigger the generation of more global Ca²⁺ release from the sarcoplasmic reticulum via Ca²⁺-induced Ca²⁺ release, and TPC2 inhibition resulted in a significant attenuation of slow skeletal muscle cells differentiation.

4. Cane M.C., et al. The two pore channel TPC2 is dispensable in pancreatic β-cells for normal Ca²⁺ dynamics and insulin secretion. Cell Calcium. 2016, 59(1): 32-40. PubMed ID: 26769314
   
   

   This article researched the effect of TPCN2 on insulin secretion by using β-cell selective deletion of the TPCN2 gene in mice. They found that TPC2 was not absolutely necessary for normal glucose- or incretin-stimulated insulin secretion from the β-cell, in contrast, it was TPCN1 might be required to support normal Ca²⁺ dynamics in response to stimulation by nutrients or incretins.

5. Patel S. and Kilpatrick B.S. Two-pore channels and disease. Biochimica et Biophysica Acta. 2018, 1865(11 Pt B): 1678-1686. PubMed ID: 29746898
   
   

   This article discussed mechanism of Ca²⁺ changes mediated by TPCs triggering or reversing disease phenotypes. They elaborated several TPCs related diseases covering Parkinson's disease, non-alcoholic fatty liver disease, Ebola infection, cancer, cardiac dysfunction, and diabetes.

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Reference

1. Patel S. and Kilpatrick B.S. (2018). Two-pore channels and disease. Biochimica et Biophysica Acta. 1865(11 Pt B): 1678-1686.

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