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Open AccessArticle

TRPC6-Mediated ERK1/2 Activation Increases Dentate Granule Cell Resistance to Status Epilepticus via Regulating Lon Protease-1 Expression and Mitochondrial Dynamics

1
Department of Anatomy and Neurobiology, College of Medicine, Hallym University, Chuncheon 24252, Korea
2
Institute of Epilepsy Research, College of Medicine, Hallym University, Chuncheon 24252, Korea
*
Author to whom correspondence should be addressed.
Cells 2019, 8(11), 1376; https://doi.org/10.3390/cells8111376
Received: 7 September 2019 / Revised: 21 October 2019 / Accepted: 30 October 2019 / Published: 1 November 2019
(This article belongs to the Special Issue Mitochondria in Health and Diseases)
Transient receptor potential canonical channel-6 (TRPC6) is one of the Ca2+-permeable non-selective cation channels. TRPC6 is mainly expressed in dentate granule cell (DGC), which is one of the most resistant neuronal populations to various harmful stresses. Although TRPC6 knockdown evokes the massive DGC degeneration induced by status epilepticus (a prolonged seizure activity, SE), the molecular mechanisms underlying the role of TRPC6 in DGC viability in response to SE are still unclear. In the present study, hyperforin (a TRPC6 activator) facilitated mitochondrial fission in DGC concomitant with increases in Lon protease-1 (LONP1, a mitochondrial protease) expression and extracellular-signal-regulated kinase 1/2 (ERK1/2) phosphorylation under physiological conditions, which were abrogated by U0126 (an ERK1/2 inhibitor) co-treatment. TRPC6 knockdown showed the opposite effects on LONP1 expression, ERK1/2 activity, and mitochondrial dynamics. In addition, TRPC6 siRNA and U0126 evoked the massive DGC degeneration accompanied by mitochondrial elongation following SE, independent of seizure severity. However, LONP1 siRNA exacerbated SE-induced DGC death without affecting mitochondrial length. These findings indicate that TRPC6-ERK1/2 activation may increase DGC invulnerability to SE by regulating LONP1 expression as well as mitochondrial dynamics. Therefore, TRPC6-ERK1/2-LONP1 signaling pathway will be an interesting and important therapeutic target for neuroprotection from various neurological diseases. View Full-Text
Keywords: dentate granule cell; epilepsy; hyperforin; LONP1; mitochondrial dynamics; neuroprotection; pilocarpine; seizure; siRNA dentate granule cell; epilepsy; hyperforin; LONP1; mitochondrial dynamics; neuroprotection; pilocarpine; seizure; siRNA
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MDPI and ACS Style

Kim, J.-E.; Park, H.; Choi, S.-H.; Kong, M.-J.; Kang, T.-C. TRPC6-Mediated ERK1/2 Activation Increases Dentate Granule Cell Resistance to Status Epilepticus via Regulating Lon Protease-1 Expression and Mitochondrial Dynamics. Cells 2019, 8, 1376.

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