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Anoctamin-1 (ANO1) is a Ca 2+ -activated Cl −  channel expressed in many types of cells. Splice variants of ANO1 have been shown to influence the biophysical properties of conductance. It has been suggested that several new antagonists of ANO1 with relatively high affinity and selectivity might be useful for experimental and, potentially, therapeutic purposes. We investigated the effects of intracellular Ca 2+  concentration ([Ca 2+ ] i ) at 100-1,000 nM, a concentration range that might be achieved in cells during physiological activation of ANO1 channels, on blockade of ANO1 channels expressed in HEK-293 cells. Whole cell and excised patch configurations of the patch-clamp technique were used to perform tests on a variety of naturally occurring splice variants of ANO1. Blockade of ANO1 currents with aminophenylthiazole (T16Ainh-A01) was highly dependent on [Ca 2+ ] i . Increasing [Ca 2+ ] i  reduced the potency of this blocker. Similar Ca 2+ -dependent effects were also observed with benzbromarone. Experiments on excised, inside-out patches showed that the diminished potency of the blockers caused by intracellular Ca 2+  might involve a competitive interaction for a common binding site or repulsion of the blocking drugs by electrostatic forces at the cytoplasmic surface of the channels. The degree of interaction between the channel blockers and [Ca 2+ ] i  depends on the splice variant expressed. These experiments demonstrate that the efficacy of ANO1 antagonists depends on [Ca 2+ ] i , suggesting a need for caution when ANO1 blockers are used to determine the role of ANO1 in physiological functions and in their use as therapeutic agents.

Influence of intracellular Ca2+ and alternative splicing on the pharmacological profile of ANO1 channels

Influence of intracellular Ca²⁺ and alternative splicing on the pharmacological profile of ANO1 channels