Targeting Two-Pore Channels: Current Progress and Future Challenges

Abstract

Two-pore channels (TPCs) are cation-permeable channels located on endolysosomal membranes and important mediators of intracellular Ca 2+ signalling. TPCs are involved in various pathophysiological processes, including cell growth and development, metabolism, and cancer progression. Most studies of TPCs have used TPC –/– cell or whole-animal models, or Ned-19, an indirect inhibitor. The TPC activation mechanism remains controversial, which has made it difficult to develop selective modulators. Recent studies of TPC structure and their interactomes are aiding the development of direct pharmacological modulators. This process is still in its infancy, but will facilitate future research and TPC targeting for therapeutical purposes. Here, we review the progress of current research into TPCs, including recent insights into their structures, functional roles, mechanisms of activation, and pharmacological modulators.

A review on possible mechanistic insights of Nitazoxanide for repurposing in COVID-19

“…This route of entry involves cleavage of viral spike glycoproteins at (S1/S2) interface by host cell surface anchored proteases, transmembrane-protease-serine-2 (TMPRSS2) and furin, exposing fusion S2 peptide available for fusion with host cell membrane ( Bestle et al, 2020 ; Z. Jin et al, 2020 ; Omolo et al, 2020 ; Ou et al, 2020 ; Xiu et al, 2020 ). Such proteolytic cleavage is dependent on the thiol-disulfide exchange mechanism catalyzed by protein disulfide isomerase (PDI) ( Diwaker et al, 2013 ; Hati and Bhattacharyya, 2020 ).…”

“…TPC2 maintains Ca 2+ homeostasis and the Ca 2+ release from this channel is controlled by nicotinic acid adenine dinucleotide phosphate (NAADP), phosphoinositide and mTOR (X. Jin et al, 2020 ; Petersen et al, 2020 ). The endolysosomal lumen serves as an important type of intracellular Ca 2+ store, containing high Ca 2+ concentration of ∼600 μM ( Alharbi and Parrington, 2019 ).…”

“…The proposed convalescent plasma therapy would find application only in severe emergencies, but is certainly not an alternative for drugs, while vaccines need time to develop (Z. Jin et al, 2020 ; Lam et al, 2020 ; H. Li et al, 2020 ). The antiviral drugs remdesivir (GS 5734) and favipiravir (Avigan®) have received restricted emergency use approval against COVID-19 ( Ethiraj, 2020 ), however search for promising therapeutics is still ongoing.…”

Determinants of Phagosomal pH During Host-Pathogen Interactions

“…The Ca 2+ accumulated by this ostensibly electroneutral exchange (two H + are thought to exchange for each Ca 2+ ) could in principle be released via conductive pathways, serving as a counter-ion. Lysosomal Ca 2+ is predominantly released via TRPML1 and, to some extent, via two-pore channels (TPC) ( Jin et al, 2020 ). Though not widely acknowledged in the literature, TPCs are considerably more permeable to Na + than Ca 2+ ( Morgan and Galione, 2014 ; Guo et al, 2017 ).…”

Roles of NAD+ and Its Metabolites Regulated Calcium Channels in Cancer

“…The TPCs have been reported to be involved in various pathophysiological processes, including cell growth and development, metabolism, and cancer progression [ 101 ]. For instance, TPC2 was observed to be overexpressed in oral squamous cell carcinoma cell lines, raising intriguing questions regarding the role of TPC2 as a driver of oncogenesis [ 102 ].…”