Extracellular hemin is a reverse use-dependent gating modifier of cardiac voltage-gated Na + channels.

Autor: Gessner G; Department of Biophysics, Center for Molecular Biomedicine, Friedrich Schiller University Jena and Jena University Hospital, Hans-Knöll-Straße 2, D-07745 Jena, Germany., Jamili M; Department of Biophysics, Center for Molecular Biomedicine, Friedrich Schiller University Jena and Jena University Hospital, Hans-Knöll-Straße 2, D-07745 Jena, Germany., Tomczyk P; Kekulé-Institute for Organic Chemistry and Biochemistry, University of Bonn, Gerhard-Domagk-Straße 1, D-53121 Bonn, Germany., Menche D; Kekulé-Institute for Organic Chemistry and Biochemistry, University of Bonn, Gerhard-Domagk-Straße 1, D-53121 Bonn, Germany., Schönherr R; Department of Biophysics, Center for Molecular Biomedicine, Friedrich Schiller University Jena and Jena University Hospital, Hans-Knöll-Straße 2, D-07745 Jena, Germany., Hoshi T; Department of Physiology, University of Pennsylvania, Philadelphia, PA 19104-6085, USA., Heinemann SH; Department of Biophysics, Center for Molecular Biomedicine, Friedrich Schiller University Jena and Jena University Hospital, Hans-Knöll-Straße 2, D-07745 Jena, Germany.
Jazyk: angličtina
Zdroj: Biological chemistry [Biol Chem] 2022 Aug 29; Vol. 403 (11-12), pp. 1067-1081. Date of Electronic Publication: 2022 Aug 29 (Print Publication: 2022).
DOI: 10.1515/hsz-2022-0194
Abstrakt: Heme (Fe 2+ -protoporphyrin IX) is a well-known protein prosthetic group; however, heme and hemin (Fe 3+ -protoporphyrin IX) are also increasingly viewed as signaling molecules. Among the signaling targets are numerous ion channels, with intracellular-facing heme-binding sites modulated by heme and hemin in the sub-µM range. Much less is known about extracellular hemin, which is expected to be more abundant, in particular after hemolytic insults. Here we show that the human cardiac voltage-gated sodium channel hNa V 1.5 is potently inhibited by extracellular hemin ( IC 50  ≈ 80 nM), while heme, dimethylhemin, and protoporphyrin IX are ineffective. Hemin is selective for hNa V 1.5 channels: hNa V 1.2, hNa V 1.4, hNa V 1.7, and hNa V 1.8 are insensitive to 1 µM hemin. Using domain chimeras of hNa V 1.5 and rat rNa V 1.2, domain II was identified as the critical determinant. Mutation N803G in the domain II S3/S4 linker largely diminished the impact of hemin on the cardiac channel. This profile is reminiscent of the interaction of some peptide voltage-sensor toxins with Na V channels. In line with a mechanism of select gating modifiers, the impact of hemin on Na V 1.5 channels is reversely use dependent, compatible with an interaction of hemin and the voltage sensor of domain II. Extracellular hemin thus has potential to modulate the cardiac function.
(© 2022 Walter de Gruyter GmbH, Berlin/Boston.)
Databáze: MEDLINE
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