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- Title
Electrophysiology of Endolysosomal Two-Pore Channels: A Current Account.
- Authors
Patel, Sandip; Yuan, Yu; Chen, Cheng-Chang; Jaślan, Dawid; Gunaratne, Gihan; Grimm, Christian; Rahman, Taufiq; Marchant, Jonathan S.
- Abstract
Two-pore channels TPC1 and TPC2 are ubiquitously expressed pathophysiologically relevant proteins that reside on endolysosomal vesicles. Here, we review the electrophysiology of these channels. Direct macroscopic recordings of recombinant TPCs expressed in enlarged lysosomes in mammalian cells or vacuoles in plants and yeast demonstrate gating by the Ca2+-mobilizing messenger NAADP and/or the lipid PI(3,5)P2. TPC currents are regulated by H+, Ca2+, and Mg2+ (luminal and/or cytosolic), as well as protein kinases, and they are impacted by single-nucleotide polymorphisms linked to pigmentation. Bisbenzylisoquinoline alkaloids, flavonoids, and several approved drugs demonstrably block channel activity. Endogenous TPC currents have been recorded from a number of primary cell types and cell lines. Many of the properties of endolysosomal TPCs are recapitulated upon rerouting channels to the cell surface, allowing more facile recording through conventional electrophysiological means. Single-channel analyses have provided high-resolution insight into both monovalent and divalent permeability. The discovery of small-molecule activators of TPC2 that toggle the ion selectivity from a Ca2+-permeable (NAADP-like) state to a Na+-selective (PI(3,5)P2-like) state explains discrepancies in the literature relating to the permeability of TPCs. Identification of binding proteins that confer NAADP-sensitive currents confirm that indirect, remote gating likely underpins the inconsistent observations of channel activation by NAADP.
- Subjects
BALANCE of payments; ELECTROPHYSIOLOGY; PLANT vacuoles; PROTEIN kinases; SINGLE nucleotide polymorphisms; ION channels
- Publication
Cells (2073-4409), 2022, Vol 11, Issue 15, p2368
- ISSN
2073-4409
- Publication type
Article
- DOI
10.3390/cells11152368