PT  - JOURNAL ARTICLE
AU  - Anna Bukiya
AU  - Jacob McMillan
AU  - Alexander Fedinec
AU  - Shivaputra Patil
AU  - Duane Miller
AU  - Charles Leffler
AU  - Abby Parrill
AU  - Alex Dopico
TI  - Cerebrovascular Dilation Via Selective Targeting of the Cholane Steroid-Recognition Site in the BK Channel β1 Subunit by a Novel Nonsteroidal Agent
AID  - 10.1124/mol.112.083519
DP  - 2013 Jan 01
TA  - Molecular Pharmacology
PG  - mol.112.083519
4099  - http://molpharm.aspetjournals.org/content/early/2013/03/01/mol.112.083519.short
4100  - http://molpharm.aspetjournals.org/content/early/2013/03/01/mol.112.083519.full
AB  - The Ca2+/voltage-gated K+ (BK) channel β1 subunit is particularly abundant in vascular smooth muscle. By determining their phenotype, BK β1 allows 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 chemical structure database similarity search using LCA as template, and a two-step reaction to generate sodium 3-hydroxyolean-12-en-30-oate (HENA). HENA activated BK (cbv1+β1) channels cloned from rat cerebral artery myocytes with potency (EC50=53 μM) similar to, and 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 channels made of cbv1+β2, β3, β4, or β1T169A, indicating this drug selectively targets β1-containing BK channels via the BK β1 steroid-sensing site. HENA (3-45 μM) dilated rat and C57BL/6 mouse pressurized cerebral arteries. Consistent with electrophysiological results, this effect was larger than that of LCA. HENA failed to dilate arteries from KCNMB1 K/O mouse, underscoring BK β1's role in HENA action. Finally, carotid artery-infusion of HENA (45 μM) dilated pial cerebral arterioles via selective BK channel-targeting. In conclusion, we have identified for the first time a non-steroidal agent that selectively activates β1-containing BK channels by targeting the steroid-sensing site in BK β1 and renders vasodilation.