title: Inhibition of TRPC6 degradation suppresses ischemic brain damage in rats.
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.affiliation: Laboratory of Neural Signal Transduction, Institute of Neuroscience, Shanghai Institutes for Biological Sciences, State Key Laboratory of Neuroscience, The Graduate School, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Wanlu
authors.initials: W
authors.lastname: Du
authors.forename: Junbo
authors.initials: J
authors.lastname: Huang
authors.forename: Hailan
authors.initials: H
authors.lastname: Yao
authors.forename: Kechun
authors.initials: K
authors.lastname: Zhou
authors.forename: Bo
authors.initials: B
authors.lastname: Duan
authors.forename: Yizheng
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002154:Calpain / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology; D008297:Male; D009474:Neurons / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D050052:TRPC Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D050052:TRPC Cation Channels; C492145:Trpc6 protein, rat; D002154:Calpain
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