Allosteric switching of Ca2+ permeability in the lysosomal ion channel TPC2 underpins biased agonist activation
Year: 2026
Type: other
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 Ca02+ 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.
Authors: Mu, Qianru, Saito, Ryo, Ozola, Franceska, Jaślan, Dawid, Chu, Pak Nin, Zaki, Afroditi Maria, Rubio-Alarcon, Marcos, Keller, Marco, Yuan, Yu, Greig, Alan, Silió, Virginia, Bracher, Franz, Biggin, Philip Charles, Brailoiu, Gabriela Cristina, Brãiloiu, Eugen, Marchant, Jonathan S., Grimm, Christian, Lambie, Eric J., Rahman, Taufiq, Patel, Sandip, :unav
Language: English
Subfield: Physiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7203757655