Exceptionally selective voltage-sensor trapping of Na_V1.5 channels by Mg-protoporphyrin impairs cancer cell migration.

ABSTRACT: The human voltage-gated sodium channel hNa_V1.5 is essential for cardiac excitability. Though underrecognized, Na_V1.5 is also expressed in multiple cancers, promoting cell migration and malignancy. hNa_V1.5 is a therapeutic target but limited pharmacological isoform specificity presents a risk of side effects via neuronal and skeletal muscle Na_V channels. Here we identify Mg²⁺-protoporphyrin IX (MgPpIX), a Mg-containing tetrapyrrole and intermediate in chlorophyll biosynthesis, as a potent inhibitor of hNa_V1.5 (IC₅₀ of 1 nM). The activity profile of various metal protoporphyrins correlates with the electrostatic potential at the metal center of the compounds. MgPpIX is specific to hNa_V1.5, as no inhibitio

SUBMITTER: Jamili M 

PROVIDER: S-EPMC12855270 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature