Neurons are the most vulnerable cells upon ischemic insults.Preservation of neuronal survival is thus important for prevention of ischemic brain injury.We report that the transient receptor potential canonical (TRPC) 6 was neuroprotective in focal cerebral ischemia.TRPC6 protein level in the neurons was greatly reduced in ischemia.This downregulation was specific for TRPC6 in the members of TRPC subfamily and mediated by calpain proteolysis.A peptide that contains a sequence spanning calpain cleavage site on TRPC6 protein specifically blocked TRPC6 degradation.Moreover, this peptide was neuroprotective against ischemic insults in both cultured neurons and animals.The level of phosphorylated cAMP-response element binding protein (pCREB) was maintained by the peptide, suggesting that the CREB signaling pathway was involved in the neuroprotective effect.Our results indicated that suppression of calpain-mediated TRPC6 degradation preserved neuronal survival and prevented ischemic brain damage.