Allosteric switching of Ca²⁺ permeability in the lysosomal ion channel TPC2 underpins biased agonist activation.

Authors

Qianru Mu, Ryo Saito, Franceska Ozola, Dawid Jaślan, Pak Nin Chu, Afroditi-Maria Zaki, Marcos Rubio-Alarcon, Marco Keller, Yu Yuan, Alan Greig, Virginia Silio, Franz Bracher, Philip C Biggin, Gabriela C Brailoiu, Eugen Brailoiu, Jonathan S Marchant, Christian Grimm, Eric J Lambie, Taufiq Rahman, Sandip Patel

Published in

The EMBO journal. Aug 07, 2026. Epub Aug 07, 2026.

Abstract

Ion channels possess selectivity filters that are hardwired to ensure the selective passage of ions. Lysosomal two-pore channels are unusual as they are able to switch their cation selectivity in an agonist-specific manner, allowing differential control of organellar activity. TPC2 is permeable to Ca²⁺ when activated by the calcium-mobilizing messenger NAADP, but largely Na⁺-selective when activated by the signaling lipid PI(3,5)P₂. Co-stimulation increases Ca²⁺ but not Na⁺ permeability; however, the molecular basis for these specificity switches is not well understood. Here we show that mutation of TPC2 residues within the distal cytosolic linker, which connects the first voltage-sensing-like domain to the pore, rendered TPC2 largely unable to discriminate its agonists and highly calcium-permeable, even in the presence of PI(3,5)P₂. This mutation induced a co-activated-like state by disrupting a network of residues that connects the linker to the activation gate. Such deregulated agonist action increased lysosomal Ca²⁺ flux and compromised locomotion and viability when expressed in C. elegans. A proximal disease-linked mutation perturbed agonist action in a similar way both in vitro and in vivo. Biased signaling through TPC2 thus proceeds through molecular determinants that are remote from the selectivity filter, affecting Ca²⁺ permeability, endo-lysosomal integrity and disease.

PMID:
42567924
Bibliographic data and abstract were imported from PubMed on 08 Aug 2026.

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