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Channels (Austin). 2017 Nov 2;11(6):624-635. doi: 10.1080/19336950.2017.1375072. Epub 2017 Oct 5.

TRPM4 activation by chemically- and oxygen deprivation-induced ischemia and reperfusion triggers neuronal death.

Author information

a Departamento de Biología , Facultad de Química y Biología, Universidad de Santiago de Chile , Santiago , Chile.
b Programa de Biología Celular y Molecular , Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile , Santiago , Chile.
c Millennium Nucleus of Ion Channels-Associated Diseases (MiNICAD) , Universidad de Chile , Santiago , Chile.
d Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile , Santiago , Chile.


Cerebral ischemia-reperfusion injury triggers a deleterious process ending in neuronal death. This process has two components, a glutamate-dependent and a glutamate-independent mechanism. In the glutamate-independent mechanism, neurons undergo a slow depolarization eventually leading to neuronal death. However, little is known about the molecules that take part in this process. Here we show by using mice cortical neurons in culture and ischemia-reperfusion protocols that TRPM4 is fundamental for the glutamate-independent neuronal damage. Thus, by blocking excitotoxicity, we reveal a slow activating, glibenclamide- and 9-phenanthrol-sensitive current, which is activated within 5 min upon ischemia-reperfusion onset. TRPM4 shRNA-based silenced neurons show a reduced ischemia-reperfusion induced current and depolarization. Neurons were protected from neuronal death up to 3 hours after the ischemia-reperfusion challenge. The activation of TRPM4 during ischemia-reperfusion injury involves the increase in both, intracellular calcium and H2O2, which may act together to produce a sustained activation of the channel.


TRPM4; glutamate-independent neuronal death; ischemia-reperfusion; oxidative stress 9-phenanthrol

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