Vascular smooth muscle BK channels limit ouabain‐induced vasocontraction: Dual role of the Na/K‐ATPase as a hub for Src‐kinase and the Na/Ca‐exchanger

Large‐conductance, calcium‐activated potassium channels (BK channels) and the Na/K‐ATPase are expressed universally in vascular smooth muscle. The Na/K‐ATPase may act via changes in the intracellular Ca2+ concentration mediated by the Na/Ca exchanger (NCX) and via Src kinase. Both pathways are known...

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Published in:	The FASEB journal Vol. 38; no. 17; pp. e70046 - n/a
Main Authors:	Orth, Tobias, Pyanova, Anastasia, Lux, Simon, Kaiser, Peter, Reinheimer, Isabel, Nielsen, Daniel Løgstrup, Khalid, Josef Ali, Rognant, Salomé, Jepps, Thomas A., Matchkov, Vladimir V., Schubert, Rudolf
Format:	Journal Article
Language:	English
Published:	United States 01-09-2024
Subjects:	Animals artery BK channel Large-Conductance Calcium-Activated Potassium Channels - metabolism Male Mesenteric Arteries - drug effects Mesenteric Arteries - metabolism Muscle Contraction - drug effects Muscle, Smooth, Vascular - drug effects Muscle, Smooth, Vascular - metabolism Na/K‐ATPase Ouabain - pharmacology Rats Rats, Wistar smooth muscle Sodium-Calcium Exchanger - metabolism Sodium-Potassium-Exchanging ATPase - metabolism src-Family Kinases - metabolism Vasoconstriction - drug effects vasocontraction BK channel Na/K‐ATPase smooth muscle vasocontraction artery
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Summary:	Large‐conductance, calcium‐activated potassium channels (BK channels) and the Na/K‐ATPase are expressed universally in vascular smooth muscle. The Na/K‐ATPase may act via changes in the intracellular Ca2+ concentration mediated by the Na/Ca exchanger (NCX) and via Src kinase. Both pathways are known to regulate BK channels. Whether BK channels functionally interact in vascular smooth muscle cells with the Na/K‐ATPase remains to be elucidated. Thus, this study addressed the hypothesis that BK channels limit ouabain‐induced vasocontraction. Rat mesenteric arteries were studied using isometric myography, FURA‐2 fluorimetry and proximity ligation assay. The BK channel blocker iberiotoxin potentiated methoxamine‐induced contractions. The cardiotonic steroid, ouabain (10−5 M), induced a contractile effect of IBTX at basal tension prior to methoxamine administration and enhanced the pro‐contractile effect of IBTX on methoxamine‐induced contractions. These facilitating effects of ouabain were prevented by the inhibition of either NCX or Src kinase. Furthermore, inhibition of NCX or Src kinase reduced the BK channel‐mediated negative feedback regulation of arterial contraction. The effects of NCX and Src kinase inhibition were independent of each other. Co‐localization of the Na/K‐ATPase and the BK channel was evident. Our data suggest that BK channels limit ouabain‐induced vasocontraction by a dual mechanism involving the NCX and Src kinase signaling. The data propose that the NCX and the Src kinase pathways, mediating the ouabain‐induced activation of the BK channel, act in an independent manner. BK channels limit cardiotonic steroid‐induced vasocontraction. Inhibition of the Na/K‐ATPase by cardiotonic steroids reduces the Na+ gradient over the cell membrane and this leads to NCX reverse activity moving Ca2+ into the cell that may activate BK channels. Interaction of cardiotonic steroids with the Na/K‐ATPase activates Srckinase that may activate BK channels. Both pathways lead to hyperpolarization and inhibition of vasocontraction.
Bibliography:	Tobias Orth and Anastasia Pyanova should be considered equally as first authors. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0892-6638 1530-6860 1530-6860
DOI:	10.1096/fj.202400628RR