NAADP-evoked Ca²⁺ signals through two-pore channel-1 require arginine residues in the first S4-S5 linker.

ABSTRACT: Two-pore channels (TPCs) are two-domain members of the voltage-gated ion channel superfamily that localize to acidic organelles. Their mechanism of activation (ligands such as NAADP/PI(3,5)P₂ versus voltage) and ion selectivity (Ca²⁺ versus Na⁺) is debated. Here we report that a cluster of arginine residues in the first domain required for selective voltage-gating of TPC1 map not to the voltage-sensing fourth transmembrane region (S4) but to a cytosolic downstream region (S4-S5 linker). These residues are conserved between TPC isoforms suggesting a generic role in TPC activation. Accordingly, mutation of residues in TPC1 but not the analogous region in the second domain prevents Ca²⁺ release by NAADP in intact cells. Our data affirm the role of T

SUBMITTER: Patel S 

PROVIDER: S-EPMC5700777 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature