TRPC6-mediated ERK1/2 phosphorylation prevents dentate granule cell degeneration via inhibiting mitochondrial...

Transient receptor potential canonical channel-6 (TRPC6) is one of Ca²⁺-permeable non-selective cation channels. In the rat hippocampus, TRPC6 expression is predominantly observed in dentate granule cells (DGC) rather than other hippocampal components. Interestingly, TRPC6 knockdown results in the massive DGC degeneration following status epilepticus (SE), although DGC is one of the resistant neuronal populations to various harmful stresses. However, the molecular events underlying the DGC degeneration induced by TRPC6 knockdown are still unclear. In the present study, TRPC6 knockdown resulted in mitochondrial elongation accompanied by reduction in dynamin-related proteins 1 (DRP1)-S616 phosphorylation. Furthermore, TRPC6 knockdown selectively decreased extracellular-signal-regulated kinase 1/2 (ERK1/2) phosphorylation. Similar to TRPC6 knockdown, ERK1/2 inhibition by U0126 evoked mitochondrial elongation with diminished DRP1-S616 phosphorylation, and facilitated SE-induced DGC degeneration independent of seizure severity. These findings indicate that TRPC6 may regulate mitochondrial dynamics via ERK1/2-mediaed DRP1 activation, which would be involved in DGC invulnerability to SE. Therefore, TRPC6 will be an interesting and important therapeutic target for neurological diseases related to impaired mitochondrial dynamics.