The key role of the central cavity in sodium transport through ligand-gated two-pore channels

Phys Chem Chem Phys. 2021 Sep 14;23(34):18461-18474. doi: 10.1039/d1cp02947a. Epub 2021 Aug 24.

Abstract

Subcellular and organellar mechanisms have manifested a prominent importance for a broad variety of processes that maintain cellular life at its most basic level. Mammalian two-pore channels (TPCs) appear to be cornerstones of these processes in endo-lysosomes by controlling delicate ion-concentrations in their interiors. With evolutionary remarkable architecture and one-of-a-kind selectivity filter, TPCs are an extremely attractive topic per se. In the light of the current COVID-19 pandemic, hTPC2 emerges to be more than attractive. As a key regulator of the endocytosis pathway, it is potentially essential for diverse viral infections in humans, as demonstrated. Here, by means of multiscale molecular simulations, we propose a model of sodium transport from the lumen to the cytosol where the central cavity works as a reservoir. Since the inhibition of hTPC2 is proven to stop SARS-CoV2 in vitro, shedding light on the hTPC2 function and mechanism is the first step towards the selection of potential inhibiting candidates.

MeSH terms

  • COVID-19
  • Ion Channel Gating*
  • Ligand-Gated Ion Channels / metabolism
  • Ligand-Gated Ion Channels / physiology*
  • Ligands
  • SARS-CoV-2 / isolation & purification
  • Sodium / metabolism*

Substances

  • Ligand-Gated Ion Channels
  • Ligands
  • Sodium