TMEM16A is the molecular basis of calcium-activated chloride channels and shows Ca2+-dependent gating. It is critical to understand how the Ca2+ sensors dynamically control the gate of TMEM16A. However, the detailed mechanism by which the calcium ions bind and open the channel is still obscure. In this study, the authors confirmed that there are two Ca2+ sensors which cooperatively couple together in TMEM16A. Our data show that mutations at both Ca2+-sensitive domains, E447Y and E702Q-E705Q, weaken the Ca2+ affinity for TMEM16A channel. The EC50 for WT, E447Y, and E702Q-E705Q are 0.53 ± 0.11, 14.5 ± 0.3, and 26.5 ± 3.6 μM, respectively. The triple mutation, including both of the Ca2+ sensors, E447Y-E702Q-E705Q, with EC50 as 55.6 ± 5.1 μM, results in much further right-shifted dose response curve than the single sensor’s mutations (E447Y, E702Q-E705Q) do, which indicates that there is a cooperation between the two Ca2+-sensitive domains. We also found that the divalent cations, both Ca2+ and Sr2+, share common mechanism of gating the TMEM16A.
The Journal of Membrane Biology – Springer Journals
Published: Dec 26, 2015
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