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

Ko, Ah-Reum; Kang, Tae‐Cheon

doi:10.1016/j.neuropharm.2017.05.004

Cited by 25 publications

(55 citation statements)

References 63 publications

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“…Figure 1 shows that TRPC6 siRNA resulted in an approximate 70% reduction of TRPC6 protein level and ERK1/2 phosphorylation in the total extract obtained from hippocampus, as compared with control (non-targeting) siRNA ( p < 0.05, respectively; Figures 1A,B and Supplementary Figure S1), although it did not affect Kv4.3, GAD67 and ERK1/2 expression levels. Consistent with our previous studies (Kim et al, 2013 ; Kim and Kang, 2015 ; Ko and Kang, 2017 ), TRPC6 expression was predominantly observed in DGC and the molecular layer of the dentate gyrus (Figure 1C ). TRPC6 knockdown decreased TRPC6 expression in the hippocampus ( p < 0.05 vs. control siRNA, Figure 1C ).…”

Section: Resultssupporting

confidence: 92%

“…Non-targeting control siRNA sequence was 5′-GCAACUAACUUCGUUAGAAUCGUUAUU-3′. In our previous study (Ko and Kang, 2017 ) and the present study, 25–50 μM of U0126 inhibited ERK1/2 phosphorylation in the hippocampus by ~50% after 7 day-over infusion. Osmotic pump was placed in a subcutaneous pocket in the interscapular region.…”

Section: Methodssupporting

confidence: 62%

“…Using this infusion system, rats were given: (1) control siRNA; (2) TRPC6 siRNA; (3) vehicle; (4) U0126 (a selective ERK1/2 inhibitor, 25 μM); (5) TRPC6 siRNA + U0126; or (6) hyperforin (a TRPC6 activator, 6 μM). The sequence of TRPC6 rat siRNA (Genolution Pharmaceuticals, Inc., Seoul, South Korea) was 5′-GGAAUAUGCUUGACUUUGGAAUGUUUU-3′ (Kim and Kang, 2015 ; Ko and Kang, 2017 ). Non-targeting control siRNA sequence was 5′-GCAACUAACUUCGUUAGAAUCGUUAUU-3′.…”

Section: Methodsmentioning

confidence: 99%

“…Transient receptor potential channel-6 (TRPC6) regulates Ca 2+ influx and extracellular signal-regulated kinase 1/2 (ERK1/2) activity in the brain and thereby participates in synaptic plasticity and neuronal survival (Li et al, 2005 ; Du et al, 2010 ; Lin et al, 2013 ; Ko and Kang, 2017 ). In the hippocampus, TRPC6 is mainly expressed in dentate granule cells (DGC), CA3 pyramidal cells and γ-aminobutyric acid (GABA)-ergic interneurons (Kim et al, 2013 ; Nagy et al, 2013 ; Kim and Kang, 2015 ; Ko and Kang, 2017 ). Recently, we have reported that TRPC6 knockdown increases DGC excitability (field excitatory postsynaptic potential-population (fEPSP) spike component), synchronization of spiking activity in the population of DGC and the seizure susceptibility in response to pilocarpine.…”

Section: Introductionmentioning

confidence: 99%

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TRPC6-mediated ERK1/2 Activation Regulates Neuronal Excitability via Subcellular Kv4.3 Localization in the Rat Hippocampus

Kim

Park

Kang

2017

Front. Cell. Neurosci.

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Recently, we have reported that transient receptor potential channel-6 (TRPC6) plays an important role in the regulation of neuronal excitability and synchronization of spiking activity in the dentate granule cells (DGC). However, the underlying mechanisms of TRPC6 in these phenomena have been still unclear. In the present study, we investigated the role of TRPC6 in subcellular localization of Kv4.3 and its relevance to neuronal excitability in the rat hippocampus. TRPC6 knockdown increased excitability and inhibitory transmission in the DGC and the CA1 neurons in response to a paired-pulse stimulus. However, TRPC6 knockdown impaired γ-aminobutyric acid (GABA)ergic inhibition in the hippocampus during and after high-frequency stimulation (HFS). TRPC6 knockdown reduced the Kv4.3 clusters in membrane fractions and its dendritic localization on DGC and GABAergic interneurons. TRPC6 knockdown also decreased extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation and the efficacy of 4-aminopyridine (4-AP) in neuronal excitability. An ERK1/2 inhibitor generated multiple population spikes in response to a paired-pulse stimulus, concomitant with reduced membrane Kv4.3 translocation. A TRPC6 activator (hyperforin) reversed the effects of TRPC knockdown, except paired-pulse inhibition. These findings provide valuable clues indicating that TRPC6-mediated ERK1/2 activation may regulate subcellular Kv4.3 localization in DGC and interneurons, which is cause-effect relationship between neuronal excitability and seizure susceptibility.

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Section: Resultssupporting

confidence: 92%

Section: Methodssupporting

confidence: 62%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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TRPC6-mediated ERK1/2 Activation Regulates Neuronal Excitability via Subcellular Kv4.3 Localization in the Rat Hippocampus

Kim

Park

Kang

2017

Front. Cell. Neurosci.

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“…Recently, we have reported that excessive mitochondrial fissions lead to apoptosis of PV cells in dentate gyrus following SE (Kim and Kang, 2017 ), while aberrant mitochondrial elongations evokes programed necrosis of CA1 neurons and dentate granule cells (Kim et al, 2014 ; Hyun et al, 2016 ; Ko and Kang, 2017 ). Consistent with these previous studies, the present data show that SE resulted in degenerations of PV cell and CA1 neurons accompanied by abnormal mitochondrial fission and fusion, respectively.…”

Section: Discussionmentioning

confidence: 99%

Differential Roles of Mitochondrial Translocation of Active Caspase-3 and HMGB1 in Neuronal Death Induced by Status Epilepticus

Kim

Kang

2018

Front. Cell. Neurosci.

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Under pathophysiological conditions, aberrant mitochondrial dynamics lead to the different types of neuronal death: excessive mitochondrial fission provokes apoptosis and abnormal mitochondrial elongation induces necrosis. However, the underlying mechanisms how the different mitochondrial dynamics result in the distinct neuronal death patterns have been elusive. In the present study, status epilepticus (SE) evoked excessive mitochondrial fission in parvalbumin (PV) cells (one of GABAergic interneurons) and abnormal mitochondrial elongation in CA1 neurons in the rat hippocampus. These impaired mitochondrial dynamics were accompanied by mitochondrial translocations of active caspase-3 and high mobility group box 1 (HMGB1) in PV cells and CA1 neurons, respectively. WY14643 (an activator of mitochondrial fission) aggravated SE-induced PV cell loss by enhancing active caspase-3 induction and its mitochondrial translocation, which were attenuated by Mdivi-1 (an inhibitor of mitochondrial fission). Mitochondrial HMGB1 import was not observed in PV cell. In contrast to PV cells, Mdivi-1 deteriorated SE-induced CA1 neuronal death concomitant with mitochondrial HMGB1 translocation, which was abrogated by WY14643. These findings suggest that SE-induced aberrant mitochondrial dynamics may be involved in translocation of active caspase-3 and HMGB1 into mitochondria, which regulate neuronal apoptosis and necrosis, respectively.

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Cellular neurobiology of hyperforin

Bouron

2023

Phytotherapy Research

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Hyperforin is a phloroglucinol derivative isolated from the medicinal plant Hypericum perforatum (St John's wort, SJW). This lipophilic biomolecule displays antibacterial, pro‐apoptotic, antiproliferative, and anti‐inflammatory activities. In addition, in vitro and in vivo data showed that hyperforin is a promising molecule with potential applications in neurology and psychiatry. For instance, hyperforin possesses antidepressant properties, impairs the uptake of neurotransmitters, and stimulates the brain derived neurotrophic factor (BDNF)/TrkB neurotrophic signaling pathway, the adult hippocampal neurogenesis, and the brain homeostasis of zinc. In fact, hyperforin is a multi‐target biomolecule with a complex neuropharmacological profile. However, one prominent pharmacological feature of hyperforin is its ability to influence the homeostasis of cations such as Ca2+, Na+, Zn2+, and H+. So far, the pathophysiological relevance of these actions is currently unknown. The main objective of the present work is to provide an overview of the cellular neurobiology of hyperforin, with a special focus on its effects on neuronal membranes and the movement of cations.

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

Cited by 25 publications

References 63 publications

TRPC6-mediated ERK1/2 Activation Regulates Neuronal Excitability via Subcellular Kv4.3 Localization in the Rat Hippocampus

TRPC6-mediated ERK1/2 Activation Regulates Neuronal Excitability via Subcellular Kv4.3 Localization in the Rat Hippocampus

Differential Roles of Mitochondrial Translocation of Active Caspase-3 and HMGB1 in Neuronal Death Induced by Status Epilepticus

Cellular neurobiology of hyperforin

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