Why the study?
Selective blockers for K2P channels are lacking because drugs preferentially bind to a conserved central cavity, creating a need to identify novel drug-binding sites and allosteric inhibition mechanisms.
The identification of a novel allosteric binding site in K2P channels provides a structural basis for designing a new class of selective potassium channel blockers.
Answers are grounded in this paper and cite their sources.
Novel allosteric site on TASK channels identified in animals; leaves open selective K2P blocker development for human arrhythmias.
Two-pore-domain potassium (K2P) channels are key regulators of many physiological and pathophysiological processes and thus emerged as promising drug targets. As for other potassium channels, there is a lack of selective blockers, since drugs preferentially bind to a conserved binding site located in the central cavity. Thus, there is a high medical need to identify novel drug-binding sites outside the conserved lipophilic central cavity and to identify new allosteric mechanisms of channel inhibition. Here, we identified a novel binding site and allosteric inhibition mechanism, disrupting the recently proposed K+-flux gating mechanism of K2P channels, which results in an unusual voltage-dependent block of leak channels belonging to the TASK subfamily. The new binding site and allosteric mechanism of inhibition provide structural and mechanistic insights into the gating of TASK channels and the basis for the drug design of a new class of potent blockers targeting specific types of K2P channels.
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Rinné et al. (2019) studied this question. Bupivacaine vs. Control (no drug) was evaluated on Voltage-dependent block of TASK-1 and TASK-3 channels.
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