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Carbon monoxide targets the pore‐forming BK alpha subunit in vascular smooth muscle Ca2+‐activated large‐conductance K+ channels
Author(s) -
Essin Kirill,
Schleifenbaum Johanna,
Luft Friedrich C.,
Gollasch Maik
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1206.5
Subject(s) - iberiotoxin , bk channel , vascular smooth muscle , chemistry , biophysics , calcium activated potassium channel , charybdotoxin , heme , vasodilation , patch clamp , hemin , heme oxygenase , potassium channel , biochemistry , membrane potential , endocrinology , receptor , biology , smooth muscle , enzyme
Carbon monoxide (CO) induces vasodilation by activating arterial smooth muscle Ca2+‐activated large‐conductance potassium (BK) channels. BK channels are composed of the pore‐forming BK alpha and auxiliary BK beta1 subunits that confer an increased sensitivity for changes in membrane potential and calcium to BK channels. To elucidate the mechanism of BK channel activation, we performed whole‐cell perforated‐patch clamp experiments in fresh tibial artery vascular smooth muscle cells (VSMC) from BK beta1 gene‐deficient (−/−) and wild‐type (+/+) mice. BK currents were measured at physiological K+ gradients. Application of hemin (3 to 10 μmol/L), a substrate of heme oxygenase, induced a 4‐fold increase in current amplitude that was blocked by iberiotoxin (100 nmol/L) in +/+ cells. The effect was similar to that observed in cells from −/− mice. We next tested the vasodilator effects of hemin. Hemin (10 μmol/L) induced similar relaxations (~ 30%) of the serotonin (300 nmol/L) preconstricted VSMC from −/− and +/+ mice. This vasorelaxation was largely inhibited by iberiotoxin (100 nmol/L). This study pinpoints the BK alpha subunit as the molecule that senses CO, which results in myocyte BK channel activation and thereby endothelial‐independent relaxation. Our notion agrees with previous studies suggesting that CO modifies the binding of reduced heme to the heme‐binding domain of the channel alpha subunit C terminus.