BK β1 subunit-dependent facilitation of ethanol inhibition of BK current and cerebral artery constriction is mediated by the β1 transmembrane domain 2

Guruprasad Kuntamallappanavar, Alejandro Dopico

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Background and Purpose: Ethanol at concentrations obtained in the circulation during moderate-heavy episodic drinking (30–60 mM) causes cerebral artery constriction in several species, including humans. In rodents, ethanol-induced cerebral artery constriction results from ethanol inhibition of large conductance voltage/Ca2+ i-gated K+ (BK) channels in cerebral artery myocytes. Moreover, the smooth muscle-abundant BK β1 accessory subunit is required for ethanol to inhibit cerebral artery myocyte BK channels under physiological Ca2+ i and voltages and thus constrict cerebral arteries. The molecular bases of these ethanol actions remain unknown. Here, we set to identify the BK β1 region(s) that mediates ethanol-induced inhibition of cerebral artery myocyte BK channels and eventual arterial constriction. Experimental Approach: We used protein biochemistry, patch-clamp on engineered channel subunits, reversible cDNA permeabilization of KCNMB1 K/O mouse arteries and artery in vitro pressurization. Key Results: Ethanol inhibition of BK current was facilitated by β1 but not β4 subunits. Furthermore, only BK complexes containing β chimeras with β1 transmembrane (TM) domains on a β4 background or with a β1 TM2 domain on a β4 background displayed ethanol responses identical to those of BK complexes including wild-type β1. Moreover, β1 TM2 itself but not other β regions were necessary for ethanol-induced cerebral artery constriction. Conclusions and Implications: BK β1 TM2 is necessary for this subunit to enable ethanol-induced inhibition of myocyte BK channels and cerebral artery constriction at physiological Ca2+ and voltages. Thus, novel agents that target β1 TM2 may be considered to counteract ethanol-induced cerebral artery constriction and associated cerebrovascular conditions.

Original languageEnglish (US)
Pages (from-to)4430-4448
Number of pages19
JournalBritish Journal of Pharmacology
Volume174
Issue number23
DOIs
StatePublished - Dec 1 2017

Fingerprint

Cerebral Arteries
Constriction
Ethanol
Large-Conductance Calcium-Activated Potassium Channels
Muscle Cells
Arteries
Biochemistry
Drinking
Smooth Muscle
Rodentia
Complementary DNA

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

BK β1 subunit-dependent facilitation of ethanol inhibition of BK current and cerebral artery constriction is mediated by the β1 transmembrane domain 2. / Kuntamallappanavar, Guruprasad; Dopico, Alejandro.

In: British Journal of Pharmacology, Vol. 174, No. 23, 01.12.2017, p. 4430-4448.

Research output: Contribution to journalArticle

@article{423d86bd4fd640b8b08ce9303d06207e,
title = "BK β1 subunit-dependent facilitation of ethanol inhibition of BK current and cerebral artery constriction is mediated by the β1 transmembrane domain 2",
abstract = "Background and Purpose: Ethanol at concentrations obtained in the circulation during moderate-heavy episodic drinking (30–60 mM) causes cerebral artery constriction in several species, including humans. In rodents, ethanol-induced cerebral artery constriction results from ethanol inhibition of large conductance voltage/Ca2+ i-gated K+ (BK) channels in cerebral artery myocytes. Moreover, the smooth muscle-abundant BK β1 accessory subunit is required for ethanol to inhibit cerebral artery myocyte BK channels under physiological Ca2+ i and voltages and thus constrict cerebral arteries. The molecular bases of these ethanol actions remain unknown. Here, we set to identify the BK β1 region(s) that mediates ethanol-induced inhibition of cerebral artery myocyte BK channels and eventual arterial constriction. Experimental Approach: We used protein biochemistry, patch-clamp on engineered channel subunits, reversible cDNA permeabilization of KCNMB1 K/O mouse arteries and artery in vitro pressurization. Key Results: Ethanol inhibition of BK current was facilitated by β1 but not β4 subunits. Furthermore, only BK complexes containing β chimeras with β1 transmembrane (TM) domains on a β4 background or with a β1 TM2 domain on a β4 background displayed ethanol responses identical to those of BK complexes including wild-type β1. Moreover, β1 TM2 itself but not other β regions were necessary for ethanol-induced cerebral artery constriction. Conclusions and Implications: BK β1 TM2 is necessary for this subunit to enable ethanol-induced inhibition of myocyte BK channels and cerebral artery constriction at physiological Ca2+ and voltages. Thus, novel agents that target β1 TM2 may be considered to counteract ethanol-induced cerebral artery constriction and associated cerebrovascular conditions.",
author = "Guruprasad Kuntamallappanavar and Alejandro Dopico",
year = "2017",
month = "12",
day = "1",
doi = "10.1111/bph.14046",
language = "English (US)",
volume = "174",
pages = "4430--4448",
journal = "British Journal of Pharmacology",
issn = "0007-1188",
publisher = "Wiley-Blackwell",
number = "23",

}

TY - JOUR

T1 - BK β1 subunit-dependent facilitation of ethanol inhibition of BK current and cerebral artery constriction is mediated by the β1 transmembrane domain 2

AU - Kuntamallappanavar, Guruprasad

AU - Dopico, Alejandro

PY - 2017/12/1

Y1 - 2017/12/1

N2 - Background and Purpose: Ethanol at concentrations obtained in the circulation during moderate-heavy episodic drinking (30–60 mM) causes cerebral artery constriction in several species, including humans. In rodents, ethanol-induced cerebral artery constriction results from ethanol inhibition of large conductance voltage/Ca2+ i-gated K+ (BK) channels in cerebral artery myocytes. Moreover, the smooth muscle-abundant BK β1 accessory subunit is required for ethanol to inhibit cerebral artery myocyte BK channels under physiological Ca2+ i and voltages and thus constrict cerebral arteries. The molecular bases of these ethanol actions remain unknown. Here, we set to identify the BK β1 region(s) that mediates ethanol-induced inhibition of cerebral artery myocyte BK channels and eventual arterial constriction. Experimental Approach: We used protein biochemistry, patch-clamp on engineered channel subunits, reversible cDNA permeabilization of KCNMB1 K/O mouse arteries and artery in vitro pressurization. Key Results: Ethanol inhibition of BK current was facilitated by β1 but not β4 subunits. Furthermore, only BK complexes containing β chimeras with β1 transmembrane (TM) domains on a β4 background or with a β1 TM2 domain on a β4 background displayed ethanol responses identical to those of BK complexes including wild-type β1. Moreover, β1 TM2 itself but not other β regions were necessary for ethanol-induced cerebral artery constriction. Conclusions and Implications: BK β1 TM2 is necessary for this subunit to enable ethanol-induced inhibition of myocyte BK channels and cerebral artery constriction at physiological Ca2+ and voltages. Thus, novel agents that target β1 TM2 may be considered to counteract ethanol-induced cerebral artery constriction and associated cerebrovascular conditions.

AB - Background and Purpose: Ethanol at concentrations obtained in the circulation during moderate-heavy episodic drinking (30–60 mM) causes cerebral artery constriction in several species, including humans. In rodents, ethanol-induced cerebral artery constriction results from ethanol inhibition of large conductance voltage/Ca2+ i-gated K+ (BK) channels in cerebral artery myocytes. Moreover, the smooth muscle-abundant BK β1 accessory subunit is required for ethanol to inhibit cerebral artery myocyte BK channels under physiological Ca2+ i and voltages and thus constrict cerebral arteries. The molecular bases of these ethanol actions remain unknown. Here, we set to identify the BK β1 region(s) that mediates ethanol-induced inhibition of cerebral artery myocyte BK channels and eventual arterial constriction. Experimental Approach: We used protein biochemistry, patch-clamp on engineered channel subunits, reversible cDNA permeabilization of KCNMB1 K/O mouse arteries and artery in vitro pressurization. Key Results: Ethanol inhibition of BK current was facilitated by β1 but not β4 subunits. Furthermore, only BK complexes containing β chimeras with β1 transmembrane (TM) domains on a β4 background or with a β1 TM2 domain on a β4 background displayed ethanol responses identical to those of BK complexes including wild-type β1. Moreover, β1 TM2 itself but not other β regions were necessary for ethanol-induced cerebral artery constriction. Conclusions and Implications: BK β1 TM2 is necessary for this subunit to enable ethanol-induced inhibition of myocyte BK channels and cerebral artery constriction at physiological Ca2+ and voltages. Thus, novel agents that target β1 TM2 may be considered to counteract ethanol-induced cerebral artery constriction and associated cerebrovascular conditions.

UR - http://www.scopus.com/inward/record.url?scp=85037167173&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85037167173&partnerID=8YFLogxK

U2 - 10.1111/bph.14046

DO - 10.1111/bph.14046

M3 - Article

VL - 174

SP - 4430

EP - 4448

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

IS - 23

ER -