Scholarlink

<p>The human voltage-gated sodium channel hNa<sub>V</sub>1.5 is essential for cardiac excitability. Though underrecognized, Na<sub>V</sub>1.5 is also expressed in multiple cancers, promoting cell migration and malignancy. hNa<sub>V</sub>1.5 is a therapeutic target but limited pharmacological isoform specificity presents a risk of side effects via neuronal and skeletal muscle Na<sub>V</sub> channels. Here we identify Mg<sup>2+</sup>-protoporphyrin IX (MgPpIX), a Mg-containing tetrapyrrole and intermediate in chlorophyll biosynthesis, as a potent inhibitor of hNa<sub>V</sub>1.5 (<i>IC</i><sub>50</sub> of 1&#xa0;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<sub>V</sub>1.5, as no inhibition of other hNa<sub>V</sub> isoforms (hNa<sub>V</sub>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<sub>V</sub> 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<sub>V</sub>1.5 and may serve as a lead compound in anti-cancer drug development.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Exceptionally selective voltage-sensor trapping of NaV1.5 channels by Mg-protoporphyrin impairs cancer cell migration

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年1月29日

查看全文
  • Mahdi Jamili,
  • Marwa Ahmed,
  • Alisa Bernert,
  • Johann Rößler,
  • Guido Gessner,
  • Roland Schönherr,
  • Toshinori Hoshi,
  • Stefan H. Heinemann

摘要

The human voltage-gated sodium channel hNaV1.5 is essential for cardiac excitability. Though underrecognized, NaV1.5 is also expressed in multiple cancers, promoting cell migration and malignancy. hNaV1.5 is a therapeutic target but limited pharmacological isoform specificity presents a risk of side effects via neuronal and skeletal muscle NaV channels. Here we identify Mg2+-protoporphyrin IX (MgPpIX), a Mg-containing tetrapyrrole and intermediate in chlorophyll biosynthesis, as a potent inhibitor of hNaV1.5 (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 hNaV1.5, as no inhibition of other hNaV isoforms (hNaV1.2, 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 NaV 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 hNaV1.5 and may serve as a lead compound in anti-cancer drug development.