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Calcium activated chloride channels (CaCCs) perform a range of roles in intracellular signalling pathways. In this review, the potential role of these channels in the myometrium is discussed. Of particular interest is the CaCC forming protein ANO1, which has recently been the subject of detailed investigation within the myometrium. It has been robustly demonstrated to promote uterine contractility, and is believed to play an important role in the progression of normal labor. However, the precise mechanism by which this occurs is not yet known. We summarise the evidence to date in support of its role in the myometrium, and consider reports of its function in other settings to gain insight into its potential intracellular role in the uterine myocyte. Finally, in light of the evidence, the future therapeutic implications of this novel tocolytic target are considered.

The functional properties and physiological roles of the calcium-activated chloride channels (CaCCs) encoded by family members of transmembrane proteins of unknown function 16 (TMEM16) have been rigorously studied. Nevertheless, a poorly understood characteristic of CaCCs, namely the channel rundown, significantly interferes electrophysiological measurements of these channels. In our studies, the rundown problem of CaCCs was circumvented by normalizing the Ca2+-induced current to the maximally-activated current within a short period of time in which the rundown was insignificant. Activation of the TMEM16A-encoded CaCC, also known as ANO1, by divalent cations Ca2+, Sr2+, Ba2+, and Mg2+ were thus characterized. Ca2+, Sr2+, and Ba2+ were found to activate the ANO1 channel with different affinities, but these three divalent cations activate current to the same maximal level. On the other hand, Mg2+ was unable to induce current in ANO1, yet, appeared to compete with Ca2+ to shift the Ca2+ concentration-dependent activation curve. We also studied the permeability of the ANO1 pore for various anions, and discovered that the anion occupancy in the pore was inversely correlated with the apparent affinity of the ANO1 inhibition by niflumic acid (NFA), a known CaCC blocker. In contrast, activating the channel by different divalent cations or the different degree of channel activation did not affect NFA inhibition, suggesting that NFA inhibits the channel by altering the pore function rather than by changing the channel gating. In conclusion, our study characterized functional properties of ANO1 without interference from channel rundown, and revealed properties of the channel that have not yet been documented.