Hemin inhibits cardiac NaV channels

Here we show that the human cardiac voltage-gated sodium channel Na_V1.5 is potently inhibited by extracellular Fe³⁺-protoporphyrin IX (hemin) (IC₅₀ ≈ 80 nM), while heme, dimethylhemin, and protoporphyrin IX are ineffective. Hemin is selective for human Na_V1.5 channels: hNa_V1.2, hNa_V1.4, hNa_V1.7, and hNa_V1.8 are insensitive to 1 µM hemin. Using domain chimeras of hNa_V1.5 and rNa_V1.2, domain II was identified as the critical determinant. Mutation N803G in the S3/S4 linker of domain II 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. The impact of hemin on Na_V1.5 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.