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Research ArticleCardiovascular

Tyrosine 450 in the BK channel pore-forming (slo1) subunit mediates cholesterol protection against alcohol-induced constriction of cerebral arteries

Kelsey North, Shivantika Bisen, Alex M Dopico and Anna N Bukiya
Journal of Pharmacology and Experimental Therapeutics August 16, 2018, jpet.118.250514; DOI: https://doi.org/10.1124/jpet.118.250514
Kelsey North
University of Tennessee HSC
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Shivantika Bisen
University of Tennessee HSC
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Alex M Dopico
University of Tennessee HSC
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Anna N Bukiya
University of Tennessee HSC
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Abstract

Alcohol (ethanol) at physiologically relevant concentrations (<100 mM) constricts cerebral arteries via inhibition of voltage-/calcium-gated potassium channels of large conductance (BK) located in vascular smooth muscle (VSM). These channels consist of channel-forming slo1 (cbv1, KCNMA1) and accessory beta1 (KCNMB1) subunits. An increase in VSM cholesterol (CLR) via either dietary CLR intake or in vitro CLR enrichment was shown to protect against endothelium-independent, alcohol-induced constriction of cerebral arteries. The molecular mechanism(s) of this protection remains unknown. Here, we demonstrate that CLR enrichment of de-endothelialized middle cerebral arteries (MCAs) of rat increased CLR content in the VSM in a concentration-dependent manner. CLR enrichment blunted MCA constriction evoked by 18-75 mM but not by 100 mM alcohol. MCA enrichment with coprostanol (COPR) also blunted vasoconstriction by 50 mM alcohol, despite the fact that COPR and CLR differ in their ability to modify several major physical properties of the bilayer. CLR protection against 50 but not 100 mM alcohol was also observed in C57BL/6 and KCNMB1 knockout (K/O) mice. Permeabilization of KCNMA1 K/O MCAs with Y450Fcbv1 totally ablated CLR, but not COPR protection against vasoconstriction by 50 mM alcohol. Thus, CLR and alcohol interact at the level of the BK channel slo1 subunit, with Y450 being critical for CLR protection against alcohol-induced vasoconstriction. We document for the first time a functional competition between CLR and alcohol in regulating cerebral artery diameter and a critical role of a single amino acid within the BK channel pore-forming subunit in controlling CLR-alcohol interaction at the organ level.

  • alcohol
  • calcium-activated potassium channels
  • cardiovascular disease
  • cholesterol
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 368 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 368, Issue 3
1 Mar 2019
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Research ArticleCardiovascular

Tyrosine 450 in the BK channel pore-forming (slo1) subunit mediates cholesterol protection against alcohol-induced constriction of cerebral arteries

Kelsey North, Shivantika Bisen, Alex M Dopico and Anna N Bukiya
Journal of Pharmacology and Experimental Therapeutics August 16, 2018, jpet.118.250514; DOI: https://doi.org/10.1124/jpet.118.250514

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Research ArticleCardiovascular

Tyrosine 450 in the BK channel pore-forming (slo1) subunit mediates cholesterol protection against alcohol-induced constriction of cerebral arteries

Kelsey North, Shivantika Bisen, Alex M Dopico and Anna N Bukiya
Journal of Pharmacology and Experimental Therapeutics August 16, 2018, jpet.118.250514; DOI: https://doi.org/10.1124/jpet.118.250514
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