Key result
AK-42 acutely and reversibly inhibited CLC-2 currents in mouse CA1 hippocampal pyramidal neurons, displaying >1,000-fold selectivity over CLC-1.
AK-42 is established as a highly selective and potent tool for investigating CLC-2 neurophysiology.
Enables selective CLC-2 research in hippocampal models; leaves open clinical translation for neurological conditions.
= 17 ± 1 nM). AK-42 displays unprecedented selectivity (>1,000-fold) over CLC-1, the closest CLC-2 homolog, and exhibits no off-target engagement against a panel of 61 common channels, receptors, and transporters expressed in brain tissue. Computational docking, validated by mutagenesis and kinetic studies, indicates that AK-42 binds to an extracellular vestibule above the channel pore. In electrophysiological recordings of mouse CA1 hippocampal pyramidal neurons, AK-42 acutely and reversibly inhibits CLC-2 currents; no effect on current is observed on brain slices taken from CLC-2 knockout mice. These results establish AK-42 as a powerful tool for investigating CLC-2 neurophysiology.
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Koster et al. (2020) studied this question. AK-42 was evaluated on CLC-2 current inhibition. AK-42 acutely and reversibly inhibited CLC-2 currents in mouse CA1 hippocampal pyramidal neurons, displaying >1,000-fold selectivity over CLC-1.
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