Faculty Collaboration Database

Convergent activation of Ca²⁺ permeability in two-pore channel 2 through distinct molecular routes. Sci Signal 2023 Aug 22;16(799):eadg0661

Date

08/22/2023

Pubmed ID

37607219

Pubmed Central ID

PMC10639088

DOI

10.1126/scisignal.adg0661

Scopus ID

2-s2.0-85168781300 (requires institutional sign-in at Scopus site)   6 Citations

Abstract

TPC2 is a pathophysiologically relevant lysosomal ion channel that is activated directly by the phosphoinositide PI(3,5)P₂ and indirectly by the calcium ion (Ca²⁺)-mobilizing molecule NAADP through accessory proteins that associate with the channel. TPC2 toggles between PI(3,5)P₂-induced, sodium ion (Na⁺)-selective and NAADP-induced, Ca²⁺-permeable states in response to these cues. To address the molecular basis of polymodal gating and ion-selectivity switching, we investigated the mechanism by which NAADP and its synthetic functional agonist, TPC2-A1-N, induced Ca²⁺ release through TPC2 in human cells. Whereas NAADP required the NAADP-binding proteins JPT2 and LSM12 to evoke endogenous calcium ion signals, TPC2-A1-N did not. Residues in TPC2 that bind to PI(3,5)P₂ were required for channel activation by NAADP but not for activation by TPC2-A1-N. The cryptic voltage-sensing region of TPC2 was required for the actions of TPC2-A1-N and PI(3,5)P₂ but not for those of NAADP. These data mechanistically distinguish natural and synthetic agonist action at TPC2 despite convergent effects on Ca²⁺ permeability and delineate a route for pharmacologically correcting impaired NAADP-evoked Ca²⁺ signals.

Author List

Saito R, Mu Q, Yuan Y, Rubio-Alarcón M, Eznarriaga M, Zhao P, Gunaratne G, Kumar S, Keller M, Bracher F, Grimm C, Brailoiu E, Marchant JS, Rahman T, Patel S

Author

Jonathan S. Marchant PhD Chair, Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Calcium
Cues
Humans
Permeability
Phosphatidylinositols
Research Personnel