Deletion of TRPC6 Attenuates NMDA Receptor-Mediated Ca2+ Entry and Ca2+-Induced Neurotoxicity Following Cerebral Ischemia and Oxygen-Glucose Deprivation
Jin Chen, Zhaozhong Li, Jeffery T. Hatcher, Qing-Hui Chen, Li Chen, Robert D. Wurster, Sic L. Chan, Zixi Cheng
Abstract
Transient receptor potential canonical 6 (TRPC6) channels are permeable to Na(+) and Ca(2+) and are widely expressed in the brain. In this study, the role of TRPC6 was investigated following ischemia/reperfusion (I/R) and oxygen-glucose deprivation (OGD). We found that TRPC6 expression was increased in wild-type (WT) mice cortical neurons following I/R and in primary neurons with OGD, and that deletion of TRPC6 reduced the I/R-induced brain infarct in mice and the OGD- /neurotoxin-induced neuronal death. Using live-cell imaging to examine intracellular Ca(2+) levels ([Ca(2+)] i ), we found that OGD induced a significant higher increase in glutamate-evoked Ca(2+) influx compared to untreated control and such an increase was reduced by TRPC6 deletion. Enhancement of TRPC6 expression using AdCMV-TRPC6-GFP infection in WT neurons increased [Ca(2+)] i in response to glutamate application compared to AdCMV-GFP control. Inhibition of N-methyl-d-aspartic acid receptor (NMDAR) with MK801 decreased TRPC6-dependent increase of [Ca(2+)] i in TRPC6 infected cells, indicating that such a Ca(2+) influx was NMDAR dependent. Furthermore, TRPC6-dependent Ca(2+) influx was blunted by blockade of Na(+) entry in TRPC6 infected cells. Finally, OGD-enhanced Ca(2+) influx was reduced, but not completely blocked, in the presence of voltage-dependent Na(+) channel blocker tetrodotoxin (TTX) and dl-α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) blocker CNQX. Altogether, we concluded that I/R-induced brain damage was, in part, due to upregulation of TRPC6 in cortical neurons. We postulate that overexpression of TRPC6 following I/R may induce neuronal death partially through TRPC6-dependent Na(+) entry which activated NMDAR, thus leading to a damaging Ca(2+) overload. These findings may provide a potential target for future intervention in stroke-induced brain damage.
Pharmacology, Toxicology and Pharmaceutical Science
2
9%
Medicine and Dentistry
2
9%
Other
3
13%
Unknown
5
22%
Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 2. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 13 April 2017.
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#15,742,933
of 25,382,440 outputs
Outputs from Frontiers in Neuroscience
#6,691
of 11,542 outputs
Outputs of similar age
#178,800
of 322,922 outputs
Outputs of similar age from Frontiers in Neuroscience
#115
of 193 outputs
Altmetric has tracked 25,382,440 research outputs across all sources so far. This one is in the 37th percentile – i.e., 37% of other outputs scored the same or lower than it.
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