Two-Pore Channels: Catalyzers of Endolysosomal Transport and Function.

Christian Grimm,Christian Wahl-Schott,Martin Biel,Cheng-Chang Chen

doi:10.3389/fphar.2017.00045

Abstract

Two-pore channels (TPCs) have recently emerged as a novel class of non-selective cation channels in the endolysosomal system. There are two members in the human genome, TPC1 and TPC2. Studies with TPC knockout and knockdown models have revealed that these channels participate in the regulation of multiple endolysosomal trafficking pathways which when dysregulated can lead to or influence the development of a range of different diseases such as lysosomal storage, metabolic, or infectious diseases. TPCs have been demonstrated to be activated by different endogenous stimuli, PI(3,5)P2 and NAADP, and ATP has been found to block TPC activation via mTOR. Loss of TPCs can lead to obesity and hypercholesterolemia, and to a slow-down of intracellular virus and bacterial toxin trafficking, it can affect VEGF-induced neoangiogenesis, autophagy, human hair pigmentation or the acrosome reaction in sperm. Moreover, physiological roles of TPCs in cardiac myocytes and pancreatic β cells have been postulated.

Highlights

Since its development by Neher and Sakmann (1976), the patch clamp technique has been successfully applied to study ion channels in the plasma membrane
In other studies it was found that luminal alkalization inhibits NAADP evoked TPC2 Ca2+ currents while PI(3,5)P2 evoked TPC2 Na+ currents are not inhibited (Schieder et al, 2010; Wang et al, 2012; Jha et al, 2014). Taken together these findings suggest that TPC1 and TPC2, despite significant similarities in sequence and function may differ substantially in their overall activation mechanisms
A role for Two-pore channels (TPCs) in promoting endolysosomal trafficking appears to be well supported by the literature

Summary

Introduction

Since its development by Neher and Sakmann (1976), the patch clamp technique has been successfully applied to study ion channels in the plasma membrane. This has undoubtedly contributed to a better understanding of the function and physiology of endolysosomal ion channels such as the TPCs. TPCs derive their name from the two pore domains that are found on each subunit.

Results

Conclusion