Cerebrovascular dilation via selective targeting of the cholane steroid-recognition site in the bk channel β1-subunit by a novel nonsteroidal agents

Anna Bukiya, Jacob E. McMillan, Alexander L. Fedinec, Shivaputra A. Patil, Duane Miller, Charles Leffler, Abby L. Parrill, Alejandro Dopico

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

The Ca21/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 1 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 cbv11 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.

Original languageEnglish (US)
Pages (from-to)1030-1044
Number of pages15
JournalMolecular Pharmacology
Volume83
Issue number5
DOIs
StatePublished - May 1 2013

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Cholanes
Large-Conductance Calcium-Activated Potassium Channels
Dilatation
Lithocholic Acid
Steroids
Cerebral Arteries
Vasodilation
Muscle Cells
Chemical Databases
Arterioles
Inbred C57BL Mouse
Vascular Smooth Muscle
Carotid Arteries
Knockout Mice
Arteries
Sodium
Phenotype

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Cite this

Cerebrovascular dilation via selective targeting of the cholane steroid-recognition site in the bk channel β1-subunit by a novel nonsteroidal agents. / Bukiya, Anna; McMillan, Jacob E.; Fedinec, Alexander L.; Patil, Shivaputra A.; Miller, Duane; Leffler, Charles; Parrill, Abby L.; Dopico, Alejandro.

In: Molecular Pharmacology, Vol. 83, No. 5, 01.05.2013, p. 1030-1044.

Research output: Contribution to journalArticle

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