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Inhibition of TRPC6 degradation suppresses ischemic brain damage in rats
Wanlu Du, … , Bo Duan, Yizheng Wang
Wanlu Du, … , Bo Duan, Yizheng Wang
Published September 1, 2010
Citation Information: J Clin Invest. 2010;120(10):3480-3492. https://doi.org/10.1172/JCI43165.
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Research Article Neuroscience Article has an altmetric score of 3

Inhibition of TRPC6 degradation suppresses ischemic brain damage in rats

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Abstract

Brain injury after focal cerebral ischemia, the most common cause of stroke, develops from a series of pathological processes, including excitotoxicity, inflammation, and apoptosis. While NMDA receptors have been implicated in excitotoxicity, attempts to prevent ischemic brain damage by blocking NMDA receptors have been disappointing. Disruption of neuroprotective pathways may be another avenue responsible for ischemic damage, and thus preservation of neuronal survival may be important for prevention of ischemic brain injury. Here, we report that suppression of proteolytic degradation of transient receptor potential canonical 6 (TRPC6) prevented ischemic neuronal cell death in a rat model of stroke. The TRPC6 protein level in neurons was greatly reduced in ischemia via NMDA receptor–dependent calpain proteolysis of the N-terminal domain of TRPC6 at Lys16. This downregulation was specific for TRPC6 and preceded neuronal death. In a rat model of ischemia, activating TRPC6 prevented neuronal death, while blocking TRPC6 increased sensitivity to ischemia. A fusion peptide derived from the calpain cleavage site in TRPC6 inhibited degradation of TRPC6, reduced infarct size, and improved behavioral performance measures via the cAMP response element–binding protein (CREB) signaling pathway. Thus, TRPC6 proteolysis contributed to ischemic neuronal cell death, and suppression of its degradation preserved neuronal survival and prevented ischemic brain damage.

Authors

Wanlu Du, Junbo Huang, Hailan Yao, Kechun Zhou, Bo Duan, Yizheng Wang

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Figure 6

TAT-C6 inhibited neuronal cell death induced by OGD.

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TAT-C6 inhibited neuronal cell death induced by OGD.
(A) Representative ...
(A) Representative images of cortical neurons incubated with 5 μM TAT-ctrl or TAT-C6 2 hours before OGD and double stained with TRPC6 antibody and TUNEL labeling 24 hours after OGD. Hoechst stain was used to label the nucleus. Scale bars: 50 μm. (B) Quantification of OGD-induced cell death (at 24 hours) in the presence of TAT-ctrl or TAT-C6. *P < 0.05 versus TAT-ctrl. (C) Immunoblots for CREB and pCREB of the extracts from OGD-treated cortical neurons receiving TAT-ctrl or TAT-C6. Right panel shows quantification of p-CREB levels (n = 3–6 cultures). *P < 0.05 versus control or TAT-ctrl. Data are presented as mean ± SEM.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 2 patents
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