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- W3023076629 abstract "TRPM2 is a tetrameric Ca2+ permeable channel involved in immunocyte respiratory burst and postischaemic neuronal death. In whole cells TRPM2 activity requires intracellular ADP ribose (ADPR) and intra- or extracellular Ca2+, but the mechanism and the binding site(s) for Ca2+ activation remain unknown. Here we study TRPM2 gating in inside-out patches while directly controlling intracellular ligand concentrations. Concentration jump experiments at various voltages, and Ca2+ dependence of steady-state single-channel gating kinetics, provide unprecedented insight into the molecular mechanism of Ca2+ activation. In patches excised from Xenopus oocytes expressing human TRPM2, co-application of intracellular ADPR and Ca2+ activated ∼50-pS non-selective cation channels; K1/2 for ADPR was ∼1μM at saturating Ca2+. Intracellular Ca2+ dependence of TRPM2 steady-state opening and closing rates (at saturating [ADPR] and low extracellular Ca2+) reveals that Ca2+ activation is a consequence of tighter binding of Ca2+ in the open- than in the closed-channel conformation. Four Ca2+ ions activate TRPM2 with a Monod-Wymann-Changeux mechanism: each binding event increases the open-closed equilibrium constant ∼33-fold, producing altogether 106-fold activation. Experiments in the presence of 1mM free Ca2+ on the extracellular side clearly show that closed channels do not sense extracellular Ca2+, but once channels have opened Ca2+ entering passively through the pore slows channel closure by keeping the “activating sites” saturated, despite rapid continuous Ca2+-free wash of the intracellular channel surface. This effect of extracellular Ca2+ on gating is gradually lost at progressively depolarized membrane potentials, where the driving force for Ca2+ influx is diminished. Thus, the activating sites lie intracellularly from the gate, but in a shielded crevice near the pore entrance. Our results suggest that in intact cells which contain micromolar ADPR even brief Ca2+ spikes likely trigger prolonged, self-sustained TRPM2 activity." @default.
- W3023076629 created "2020-05-13" @default.
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- W3023076629 date "2009-02-01" @default.
- W3023076629 modified "2023-09-26" @default.
- W3023076629 title "Ca2+ Activates TRPM2 Channels By Binding In Deep Crevices Near The Pore, But Intracellularly Of The Gate" @default.
- W3023076629 doi "https://doi.org/10.1016/j.bpj.2008.12.2922" @default.
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