Patel, S;
Churamani, D;
Brailoiu, E;
(2017)
NAADP-evoked Ca2+ signals through two-pore channel-1 require arginine residues in the first S4-S5 linker.
Cell Calcium
, 68
pp. 1-4.
10.1016/j.ceca.2017.09.003.
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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 (Ca(2+) 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 Ca(2+) release by NAADP in intact cells. Our data affirm the role of TPCs in NAADP-mediated Ca(2+) signalling and unite differing models of channel activation through identification of common domain-specific residues.
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