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  • Bilirubin gates the TRPM2 channel as a direct agonist to exacerbate ischemic brain damage.

Bilirubin gates the TRPM2 channel as a direct agonist to exacerbate ischemic brain damage.

Neuron (2023-03-16)
Han-Wei Liu, Li-Na Gong, Ke Lai, Xia-Fei Yu, Zhen-Qi Liu, Ming-Xian Li, Xin-Lu Yin, Min Liang, Hao-Song Shi, Lin-Hua Jiang, Wei Yang, Hai-Bo Shi, Lu-Yang Wang, Shan-Kai Yin
ABSTRACT

Stroke prognosis is negatively associated with an elevation of serum bilirubin, but how bilirubin worsens outcomes remains mysterious. We report that post-, but not pre-, stroke bilirubin levels among inpatients scale with infarct volume. In mouse models, bilirubin increases neuronal excitability and ischemic infarct, whereas ischemic insults induce the release of endogenous bilirubin, all of which are attenuated by knockout of the TRPM2 channel or its antagonist A23. Independent of canonical TRPM2 intracellular agonists, bilirubin and its metabolic derivatives gate the channel opening, whereas A23 antagonizes it by binding to the same cavity. Knocking in a loss of binding point mutation for bilirubin, TRPM2-D1066A, effectively antagonizes ischemic neurotoxicity in mice. These findings suggest a vicious cycle of stroke injury in which initial ischemic insults trigger the release of endogenous bilirubin from injured cells, which potentially acts as a volume neurotransmitter to activate TRPM2 channels, aggravating Ca2+-dependent brain injury.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Bilirubin, ≥98% (EmM/453 = 60), powder
Sigma-Aldrich
(+)-Bicuculline, ≥97.0% (TLC)
Sigma-Aldrich
PARP Inhibitor VIII, PJ34, The PARP Inhibitor VIII, PJ34, also referenced under CAS 344458-15-7, controls the biological activity of PARP. This small molecule/inhibitor is primarily used for Cell Structure applications.
Sigma-Aldrich
NBQX hydrate, powder, ≥98% (HPLC)
Sigma-Aldrich
DL-2-Amino-5-phosphonopentanoic acid, solid
Sigma-Aldrich
HEPES, ≥99.5% (titration)