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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 4

NMDAR-mediated calpain proteolysis of TRPC6 in modeled ischemia.

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NMDAR-mediated calpain proteolysis of TRPC6 in modeled ischemia.
(A) TRP...
(A) TRPC6 was proteolyzed by calpain. Immunoblots of the rat brain lysates incubated with Ca2+ in the presence or absence (No inh.) of the indicated agents using the indicated antibodies. Calpeptin, 20 μM; leupeptin, 100 μM; PMSF, 100 μM; EGTA, 5 mM. Right panel: quantification of TRPC6 levels (n = 3). **P < 0.01 versus control. (B) Immunoblots for TRPC6 in cortical neurons 24 hours after OGD in the presence of vehicle (Veh.), calpeptin (20 μM), or MDL28170 (MDL, 60 μM). Right panel: quantification of TRPC6 levels (n = 3). *P < 0.05; **P < 0.01 versus vehicle (TRPC6 antibody: Sigma-Aldrich). (C) Quantification of OGD-induced cell death (at 24 hours) in the presence of vehicle, calpeptin, or MDL28170 (n = 3). **P < 0.01 versus vehicle. (D) 2 calpain siRNA prevented OGD-induced TRPC6 degradation. Lower panel: quantification of TRPC6 levels (n = 3). **P < 0.01 versus nonsense siRNA (NS). (E) 2 NR1 siRNA inhibited OGD-induced TRPC6 degradation. Right panel: quantification of TRPC6 levels (n = 3) **P < 0.01 versus NS. Calpeptin (F) or memantine (G) suppressed the ischemia-induced TRPC6 degradation as analyzed by immunoblots. Quantifications of TRPC6 levels are shown on the lower panel. R12, 12 hours after reperfusion (n = 3). **P < 0.01 versus vehicle. 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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