SKA‐111, a positive KCa channel gating modulator with selectivity for KCa3.1

Abstract

Intermediate‐conductance KCa3.1 and small‐conductance KCa2.3 channels are co‐expressed in vascular endothelium, where both channels contribute to endothelium‐derived hyperpolarization (EDH) vasodilator responses. However, despite having very similar biophysical properties, KCa3.1 and KCa2.3 seem to play different roles in EDH. While KCa3.1 channels are predominantly localized to endothelial cell projections and are activated by Ca2+ released from the ER, KCa2.3 channels co‐localize with TRP channels and have been shown to be involved in sheer‐stress induced vasodilation. It therefore is perceivable that selective activation of either channel could differentially affect endothelial functions and blood pressure. However, the currently available KCa channel activators like EBIO, NS309 and SKA‐31 at most display 5–10 fold selectivity for KCa3.1 over KCa2.3 making it difficult to interpret in vivo observations made with these compounds. We here report the design of a new benzothiazole, SKA‐111, which displays 160‐fold selectivity for KCa3.1 (EC50 = 30 nM) over KCa2.3 (EC50 = 5 μM) in whole‐cell patch‐clamp experiments. Similar to the prototypical KCa2/3 channel activator EBIO, SKA‐111 is a positive‐gating modulator, which shifts the calcium‐dose response curve of KCa3.1 to the left, making the channel apparently more sensitive to calcium activation. We propose SKA‐111 as a novel pharmacological tool to study the role of KCa3.1 in EDH responses.Supported by R21 NS072585 from the National Institute of Health