ArticleMolecular pharmacology2013
Cerebrovascular dilation via selective targeting of the cholane steroid-recognition site in the BK channel β1-subunit by a novel nonsteroidal agent.
Article in Molecular pharmacology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
What it found
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Who cites it
34 citing papers in PubMed, 42 citations in OpenAlex.
- Site and mechanism of BK channel inhibition and cerebral artery constriction by pregnenolone.Pharmacological research · 2026Article
- Pharmacological Relevance of β-, γ-, and LINGO Auxiliary Subunits in BK Channel Modulation.ChemMedChem · 2026Review
- Potassium channels in vascular smooth muscle cells.Physiological reviews · 2026Review
- Toluene is a cerebral artery constrictor acting via BK channels.Neuropharmacology · 2025Article
- Ethanol alters mechanosensory habituation in C. elegans by way of the BK potassium channel through a novel mechanism.PloS one · 2025Article
- Progesterone activation of βNature communications · 2023Article
- Differential Functional Contribution of BK Channel Subunits to Aldosterone-Induced Channel Activation in Vascular Smooth Muscle and Eventual Cerebral Artery Dilation.International journal of molecular sciences · 2023Article
- Interspecies and regional variability of alcohol action on large cerebral arteries: regulation by KCNMB1 proteins.American journal of physiology. Regulatory, integrative and comparative physiology · 2023Article
- Discovery of agonist-antagonist pairs for the modulation of CaBioorganic & medicinal chemistry · 2022Article
- BK channel-forming slo1 proteins mediate the brain artery constriction evoked by the neurosteroid pregnenolone.Neuropharmacology · 2021Article
- Overview of bile acid signaling in the cardiovascular system.World journal of clinical cases · 2021Review
- Celastrol Dilates and Counteracts Ethanol-Induced Constriction of Cerebral Arteries.The Journal of pharmacology and experimental therapeutics · 2020Article
- The molecular nature of the 17β-Estradiol binding site in the voltage- and CaScientific reports · 2019Article
- Extra-endothelial TRPV1 channels participate in alcohol and caffeine actions on cerebral artery diameter.Alcohol (Fayetteville, N.Y.) · 2018Article
- Tyrosine 450 in the Voltage- and Calcium-Gated Potassium Channel of Large Conductance Channel Pore-Forming (slo1) Subunit Mediates Cholesterol Protection against Alcohol-Induced Constriction of Cerebral Arteries.The Journal of pharmacology and experimental therapeutics · 2018Article
- Calcium- and voltage-gated BK channels in vascular smooth muscle.Pflugers Archiv : European journal of physiology · 2018Review
- Activation of human smooth muscle BK channels by hydrochlorothiazide requires cell integrity and the presence of BK βActa pharmacologica Sinica · 2018Article
- Article
- BK β1 subunit-dependent facilitation of ethanol inhibition of BK current and cerebral artery constriction is mediated by the β1 transmembrane domain 2.British journal of pharmacology · 2017Article
- Restoration of the response of the middle cerebral artery of the rat to acidosis in hyposmotic hyponatremia by the opener of large-conductance calcium sensitive potassium channels (BKJournal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2017Article
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
The Ca(2+)/voltage-gated K(+) large conductance (BK) channel β1 subunit is particularly abundant in vascular smooth muscle. By determining their phenotype, BK β1 allows the BK channels to reduce myogenic tone, facilitating vasodilation. The endogenous steroid lithocholic acid (LCA) dilates cerebral arteries via BK channel activation, which requires recognition by a BK β1 site that includes Thr169. Whether exogenous nonsteroidal agents can access this site to selectively activate β1-containing BK channels and evoke vasodilation remain unknown. We performed a chemical structure database similarity search using LCA as a template, along with a two-step reaction to generate sodium 3-hydroxyolean-12-en-30-oate (HENA). HENA activated the BK (cbv1 + β1) channels cloned from rat cerebral artery myocytes with a potency (EC₅₀ = 53 μM) similar to and an efficacy (×2.5 potentiation) significantly greater than that of LCA. This HENA action was replicated on native channels in rat cerebral artery myocytes. HENA failed to activate the channels made of cbv1 + β2, β3, β4, or β1T169A, indicating that this drug selectively targets β1-containing BK channels via the BK β1 steroid-sensing site. HENA (3-45 μM) dilated the rat and C57BL/6 mouse pressurized cerebral arteries. Consistent with the electrophysiologic results, this effect was larger than that of LCA. HENA failed to dilate the arteries from the KCNMB1 knockout mouse, underscoring BK β1's role in HENA action. Finally, carotid artery-infusion of HENA (45 μM) dilated the pial cerebral arterioles via selective BK-channel targeting. In conclusion, we have identified for the first time a nonsteroidal agent that selectively activates β1-containing BK channels by targeting the steroid-sensing site in BK β1, rendering vasodilation.
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Registered trials
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.