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Updated: Jun 26, 2026

Modeling Neuronal Death and Degeneration in Mouse Primary Cerebellar Granule Neurons
Published on: November 6, 2017
Structural mechanism of Necrocide 1 activation of human TRPM4 that triggers necrosis by sodium overload
Celso M Teixeira-Duarte1,2, Wan Fu3, Weizhong Zeng1,2
1Howard Hughes Medical Institute and Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Abstract:
The small molecule Necrocide 1 (NC1) constitutively activates human TRPM4, triggering Na⁺ influx and leading to necrotic cell death, a process termed Necrosis by Sodium Overload (NECSO). NC1 activation is specific to human TRPM4 and does not affect most of the other mammalian TRPM4 orthologs. Here, we elucidate the molecular mechanism underlying NC1 activation and its species-specific selectivity for human TRPM4 using a combination of single-particle cryo-EM, electrophysiology, and cell death assays. We identify the NC1-binding site and the key molecular determinants responsible for channel activation. In addition, we explain the insensitivity of mouse TRPM4 to NC1 and pinpoint specific residues that define NC1 specificity for human TRPM4. Given the upregulation of TRPM4 in various human cancers, our mechanistic insights into NC1 activation and specificity provide a framework for the potential development of cancer therapeutics targeting TRPM4-mediated necrosis.
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