The Natural Compound Cinnamaldehyde is a Novel Activator of Calcium-Activated Chloride Channel

Calcium-activated chloride channels (CaCCs) play important roles in a multitude of physiological processes, and in many cells types, TMEM16A was identified as the molecular basis of CaCC. Abnormal CaCC function has been implicated in variety of diseases, which reinforces the need for modulators of CaCCs/TMEM16A. However, there are few specific, clinical modulators of CaCCs. Here, we identified a potent novel activator of TMEM16A from a bank of traditional Chinese medicines (TCM) and explored its mechanism of activation by laser confocal scanning microscopy and patch clamping. Fluorescence data demonstrated that among the 36 tested TCM medicines, one compound, cinnamaldehyde (CA), can activate the TMEM16A channel in a dose-dependent manner. To determine the mechanism by which CA activates the TMEM16A channel, we performed an excised patch clamp experiment and measured the intracellular calcium concentration in fluorescence experiments. Our data show that CA activates TMEM16A channels by elevating the intracellular concentrations of calcium ions. The results of the whole-cell patch clamping showed that CA dose-dependently activates these channels, with an EC₅₀ of 9.73 ± 5.64 µM at + 80 mV, and prolongs the deactivation of TMEM16A. Finally, we found that CA can strengthen contractions of the ileum in guinea pigs by activating TMEM16A. The results demonstrate that CA is a novel, natural activator of TMEM16A.