Exceptionally selective voltage-sensor trapping of NaV1.5 channels by Mg-protoporphyrin impairs cancer cell migration
Abstract
Abstract The human voltage-gated sodium channel hNa V 1.5 is essential for cardiac excitability. Though underrecognized, Na V 1.5 is also expressed in multiple cancers, promoting cell migration and malignancy. hNa V 1.5 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 Mg 2+ -protoporphyrin IX (MgPpIX), a Mg-containing tetrapyrrole and intermediate in chlorophyll biosynthesis, as a potent inhibitor of hNa V 1.5 ( IC 50 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 V 1.5, as no inhibition of other hNa V isoforms (hNa V 1.2, 1.4, 1.7, 1.8) was detected. A mutagenesis study and structural modeling reveals that MgPpIX stabilizes the domain-II voltage sensor in the deactivated conformation, with residues E795 and N803 being relevant determinants. MgPpIX also inhibits native Na V channels in breast cancer MDA-MB-231 and colorectal carcinoma SW-480 cell lines, and suppresses cell migration. MgPpIX is an exceptionally potent and specific inhibitor of hNa V 1.5 and may serve as a lead compound in anti-cancer drug development.
Read the paper
Related studies
- Noninvasive and Point-of-Care Surface-Enhanced Raman Scattering (SERS)-Based Breathalyzer for Mass Screening of Coronavirus Disease 2019 (COVID-19) under 5 min
- De Novo Transcriptome Analysis and Detection of Antimicrobial Peptides of the American Cockroach Periplaneta americana (Linnaeus)
- Molecular Characterization and Expression Profiling of Tomato GRF Transcription Factor Family Genes in Response to Abiotic Stresses and Phytohormones
- Assembly of Tight Junction Strands: Claudin-10b and Claudin-3 Form Homo Tetrameric Building Blocks that Polymerise in a Channel-Independent Manner
- Update of the Pompe variant database for the prediction of clinical phenotypes: Novel disease‐associated variants, common sequence variants, and results from newborn screening
- Machine Learning-Based SERS Chemical Space for Two-Way Prediction of Structures and Spectra of Untrained Molecules
Go deeper in Evidence Hub
Evidence Hub adds a study data sheet (design, sample size, evidence level, key numbers), an AI summary and a chat grounded in the paper's text.