TRPC6-Mediated ERK1/2 Activation Increases Dentate Granule Cell Resistance to Status Epilepticus via Regulating Lon Protease-1 Expression and Mitochondrial Dynamics
Transient receptor potential canonical channel-6 (TRPC6) is one of the Ca<sup>2+</sup>-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 kno...
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MDPI AG
2019-11-01
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| Online Access: | https://www.mdpi.com/2073-4409/8/11/1376 |
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| author | Ji-Eun Kim Hana Park Seo-Hyeon Choi Min-Jeong Kong Tae-Cheon Kang |
| author_facet | Ji-Eun Kim Hana Park Seo-Hyeon Choi Min-Jeong Kong Tae-Cheon Kang |
| author_sort | Ji-Eun Kim |
| collection | DOAJ |
| description | Transient receptor potential canonical channel-6 (TRPC6) is one of the Ca<sup>2+</sup>-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. |
| first_indexed | 2024-03-12T20:23:39Z |
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| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-12T20:23:39Z |
| publishDate | 2019-11-01 |
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| spelling | doaj.art-a098727eb7e049b3b11bba45f76e6dfd2023-08-02T00:45:04ZengMDPI AGCells2073-44092019-11-01811137610.3390/cells8111376cells8111376TRPC6-Mediated ERK1/2 Activation Increases Dentate Granule Cell Resistance to Status Epilepticus via Regulating Lon Protease-1 Expression and Mitochondrial DynamicsJi-Eun Kim0Hana Park1Seo-Hyeon Choi2Min-Jeong Kong3Tae-Cheon Kang4Department of Anatomy and Neurobiology, College of Medicine, Hallym University, Chuncheon 24252, KoreaDepartment of Anatomy and Neurobiology, College of Medicine, Hallym University, Chuncheon 24252, KoreaDepartment of Anatomy and Neurobiology, College of Medicine, Hallym University, Chuncheon 24252, KoreaDepartment of Anatomy and Neurobiology, College of Medicine, Hallym University, Chuncheon 24252, KoreaDepartment of Anatomy and Neurobiology, College of Medicine, Hallym University, Chuncheon 24252, KoreaTransient receptor potential canonical channel-6 (TRPC6) is one of the Ca<sup>2+</sup>-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.https://www.mdpi.com/2073-4409/8/11/1376dentate granule cellepilepsyhyperforinlonp1mitochondrial dynamicsneuroprotectionpilocarpineseizuresirna |
| spellingShingle | Ji-Eun Kim Hana Park Seo-Hyeon Choi Min-Jeong Kong Tae-Cheon Kang TRPC6-Mediated ERK1/2 Activation Increases Dentate Granule Cell Resistance to Status Epilepticus via Regulating Lon Protease-1 Expression and Mitochondrial Dynamics Cells dentate granule cell epilepsy hyperforin lonp1 mitochondrial dynamics neuroprotection pilocarpine seizure sirna |
| title | TRPC6-Mediated ERK1/2 Activation Increases Dentate Granule Cell Resistance to Status Epilepticus via Regulating Lon Protease-1 Expression and Mitochondrial Dynamics |
| title_full | TRPC6-Mediated ERK1/2 Activation Increases Dentate Granule Cell Resistance to Status Epilepticus via Regulating Lon Protease-1 Expression and Mitochondrial Dynamics |
| title_fullStr | TRPC6-Mediated ERK1/2 Activation Increases Dentate Granule Cell Resistance to Status Epilepticus via Regulating Lon Protease-1 Expression and Mitochondrial Dynamics |
| title_full_unstemmed | TRPC6-Mediated ERK1/2 Activation Increases Dentate Granule Cell Resistance to Status Epilepticus via Regulating Lon Protease-1 Expression and Mitochondrial Dynamics |
| title_short | TRPC6-Mediated ERK1/2 Activation Increases Dentate Granule Cell Resistance to Status Epilepticus via Regulating Lon Protease-1 Expression and Mitochondrial Dynamics |
| title_sort | trpc6 mediated erk1 2 activation increases dentate granule cell resistance to status epilepticus via regulating lon protease 1 expression and mitochondrial dynamics |
| topic | dentate granule cell epilepsy hyperforin lonp1 mitochondrial dynamics neuroprotection pilocarpine seizure sirna |
| url | https://www.mdpi.com/2073-4409/8/11/1376 |
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