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Abstract
The calcium-activated chloride channel TMEM16A is involved in many physiological processes,
and insufficient function of TMEM16A may lead to the occurrence of various diseases.
Therefore, TMEM16A activators are supposed to be potentially useful for treatment
of TMEM16A downregulation-inducing diseases. However, the TMEM16A activators are relatively
rare, and the underlying activation mechanism of them is unclear. In the previous
work, we have proved that ginsenoside Rb1 is a TMEM16A activator. In this work, we
explored the activation mechanism of ginsenoside analogs on TMEM16A through analyzing
the interactions between six ginsenoside analogs and TMEM16A. We identified GRg2 and
GRf can directly activate TMEM16A by screening five novel ginsenosids analogs (GRb2,
GRf, GRg2, GRh2, and NGR1). Isolated guinea pig ileum assay showed both GRg2 and GRf
increased the amplitude and frequency of ileum contractions. We explored the molecular
mechanisms of ginsenosides activating TMEM16A by combining molecular simulation with
electrophysiological experiments. We proposed a TMEM16A activation process model based
on the results, in which A697 on TM7 and L746 on TM8 bind to the isobutenyl of ginsenosides
through hydrophobic interaction to fix the spatial location of ginsenosides. N650
on TM6 and E705 on TM7 bind to ginsenosides through electrostatic interaction, which
causes the inner half of α-helix 6 to form physical contact with ginsenosides and
leads to the pore opening. It should be emphasized that TMEM16A can be activated by
ginsenosides only when both the above two conditions are satisfied. This is the first,
to our knowledge, report of TMEM16A opening process activated by small-molecule activators.
The mechanism of ginsenosides activating TMEM16A will provide important clues for
TMEM16A gating mechanism and for new TMEM16A activators screening.