ArticleProceedings of the National Academy of Sciences of the United States of America2012
Molecular mechanism of pharmacological activation of BK channels.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed.
- Big conductance calcium-activated potassium channel openers control spasticity without sedation.British journal of pharmacology · 2017Trial
- The BK channel-NS1619 agonist complex reveals molecular insights into allosteric activation gating.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Article
- Pharmacological activation of BK channels protects against LPS-induced pneumonia.Scientific reports · 2025Article
- Activation mechanism and novel binding sites of the BKLife science alliance · 2024Article
- Structural mapping of patient-associated KCNMA1 gene variants.Biophysical journal · 2024Article
- Loss of anoctamin 1 reveals a subtle role for BK channels in lymphatic muscle action potentials.The Journal of physiology · 2024Article
- Emodepside: the anthelmintic's mode of action and toxicity.Frontiers in parasitology · 2024Review
- Lysosomal BK channels facilitate silica-induced inflammation in macrophages.Inhalation toxicology · 2024Article
- TRPML3/BK complex promotes autophagy and bacterial clearance by providing a positive feedback regulation of mTOR via PI3P.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Discovery of agonist-antagonist pairs for the modulation of CaBioorganic & medicinal chemistry · 2022Article
- Novel Labdane Diterpenes-Based Synthetic Derivatives: Identification of a Bifunctional Vasodilator That Inhibits CaMarine drugs · 2022Article
- VietnameseMolecules (Basel, Switzerland) · 2022Article
- Alternative Targets for Modulators of Mitochondrial Potassium Channels.Molecules (Basel, Switzerland) · 2022Review
- BK Channel in the Physiology and in the Cancer of Pancreatic Duct: Impact and Reliability of BK Openers.Frontiers in pharmacology · 2022Review
- State-dependent inhibition of BK channels by the opioid agonist loperamide.The Journal of general physiology · 2021Article
- Article
- Molecular mechanism of BK channel activation by the smooth muscle relaxant NS11021.The Journal of general physiology · 2020Article
- The action of a BK channel opener.The Journal of general physiology · 2020Article
- Loss-of-function BK channel mutation causes impaired mitochondria and progressive cerebellar ataxia.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
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Authors and funding
7 authors.
Funding
Abstract
Large-conductance voltage- and Ca(2+)-activated K(+) (Slo1 BK) channels serve numerous cellular functions, and their dysregulation is implicated in various diseases. Drugs activating BK channels therefore bear substantial therapeutic potential, but their deployment has been hindered in part because the mode of action remains obscure. Here we provide mechanistic insight into how the dehydroabietic acid derivative Cym04 activates BK channels. As a representative of NS1619-like BK openers, Cym04 reversibly left-shifts the half-activation voltage of Slo1 BK channels. Using an established allosteric BK gating model, the Cym04 effect can be simulated by a shift of the voltage sensor and the ion conduction gate equilibria toward the activated and open state, respectively. BK activation by Cym04 occurs in a splice variant-specific manner; it does not occur in such Slo1 BK channels using an alternative neuronal exon 9, which codes for the linker connecting the transmembrane segment S6 and the cytosolic RCK1 domain--the S6/RCK linker. In addition, Cym04 does not affect Slo1 BK channels with a two-residue deletion within this linker. Mutagenesis and model-based gating analysis revealed that BK openers, such as Cym04 and NS1619 but not mallotoxin, activate BK channels by functionally interacting with the S6/RCK linker, mimicking site-specific shortening of this purported passive spring, which transmits force from the cytosolic gating ring structure to open the channel's gate.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.