PLC‐dependent intracellular Ca2+ release was associated with C6‐ceramide‐induced inhibition of Na+ current in rat granule cells

Liu, Zheng; Fei, Xiao-Wei; Fang, Yan-Jia; Shi, Wenjie; Zhang, Yu‐Qiu; Mei, Yan‐Ai

doi:10.1111/j.1471-4159.2008.05562.x

Cited by 7 publications

(10 citation statements)

References 52 publications

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“…Cerebellar GCs grown in primary culture express tetrodotoxin (TTX)-sensitive Na V channels which are responsible for action potentials (APs) and for the code relay in the cerebellar circuitry [16], [17]. Cerebellar GCs are widely used as a model for neuronal cell development and apoptosis [18]–[20].…”

Section: Introductionmentioning

confidence: 99%

“…We have previously shown that the I Na densities of cerebellar GCs are modulated by the lipid products ceramide and arachidonic acid (AA). Ceramide reduces the I Na of cerebellar GCs by increasing calcium release through the ryanodine-sensitive Ca 2+ receptor [21] while elevation in intracellular AA levels increases the I Na of cerebellar GCs through the PGE 2 -mediated activation of the cAMP/PKA pathway [22]. The present study was conducted to determine whether exposure to ELF-EMF influences the Na + channels of cerebellar GCs and, if so, whether this effect is mediated by changes in ceramide and/or arachidonic acid.…”

Section: Introductionmentioning

confidence: 99%

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Exposure to Extremely Low-Frequency Electromagnetic Fields Modulates Na+ Currents in Rat Cerebellar Granule Cells through Increase of AA/PGE2 and EP Receptor-Mediated cAMP/PKA Pathway

Liu

Fang

et al. 2013

PLoS ONE

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Although the modulation of Ca2+ channel activity by extremely low-frequency electromagnetic fields (ELF-EMF) has been studied previously, few reports have addressed the effects of such fields on the activity of voltage-activated Na+ channels (Nav). Here, we investigated the effects of ELF-EMF on Nav activity in rat cerebellar granule cells (GCs). Our results reveal that exposing cerebellar GCs to ELF-EMF for 10–60 min significantly increased Nav currents (I Na) by 30–125% in a time- and intensity-dependent manner. The Nav channel steady-state activation curve, but not the steady-state inactivation curve, was significantly shifted (by 5.2 mV) towards hyperpolarization by ELF-EMF stimulation. This phenomenon is similar to the effect of intracellular application of arachidonic acid (AA) and prostaglandin E2 (PGE2) on I Na in cerebellar GCs. Increases in intracellular AA, PGE2 and phosphorylated PKA levels in cerebellar GCs were observed following ELF-EMF exposure. Western blottings indicated that the NaV 1.2 protein on the cerebellar GCs membrane was increased, the total expression levels of NaV 1.2 protein were not affected after exposure to ELF-EMF. Cyclooxygenase inhibitors and PGE2 receptor (EP) antagonists were able to eliminate this ELF-EMF-induced increase in phosphorylated PKA and I Na. In addition, ELF-EMF exposure significantly enhanced the activity of PLA2 in cerebellar GCs but did not affect COX-1 or COX-2 activity. Together, these data demonstrate for the first time that neuronal I Na is significantly increased by ELF-EMF exposure via a cPLA2 AA PGE2 EP receptors PKA signaling pathway.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Exposure to Extremely Low-Frequency Electromagnetic Fields Modulates Na+ Currents in Rat Cerebellar Granule Cells through Increase of AA/PGE2 and EP Receptor-Mediated cAMP/PKA Pathway

Liu

Fang

et al. 2013

PLoS ONE

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“…GCs (granule cells) occupy a key position in the cerebellumcortex circuitry, forming the input layer of the major cerebellar afferent system. Cerebellar GCs grown in primary culture express TTX (tetrodotoxin)-sensitive Na V channels that determine the discharge of the GC action potential and the code relayed into the cerebellar circuitry [22,23]. Therefore understanding the mechanisms of how GC Na V channel activity is regulated is of particular importance.…”

Section: Introductionmentioning

confidence: 99%

Arachidonic acid modulates Na+ currents by non-metabolic and metabolic pathways in rat cerebellar granule cells

Fang

Zhou

Gao

et al. 2011

Biochemical Journal

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AA (arachidonic acid), which possesses both neurotoxic and neurotrophic activities, has been implicated as a messenger in both physiological and pathophysiological processes. In the present study, we investigated the effects of both extracellular and intracellular application of AA on the activity of Na(V) (voltage-gated Na(+) channels) in rat cerebellar GCs (granule cells). The extracellular application of AA inhibited the resultant I(Na) (Na(V) current), wherein the current-voltage curve shifted to a negative voltage direction. Because this effect could be reproduced by treating the GCs with ETYA (eicosa-5,8,11,14-tetraynoic acid) or a membrane-impermeable analogue of AA, AA-CoA (arachidonoyl coenzyme A), we inferred that AA itself exerted the observed modulatory effects on I(Na). In contrast, intracellular AA significantly augmented the elicited I(Na) peak when the same protocol that was used for extracellular AA was followed. The observed I(Na) increase that was induced by intracellular AA was mimicked by the AA cyclo-oxygenase metabolite PGE(2) (prostaglandin E(2)), but not by ETYA. Furthermore, cyclo-oxygenase inhibitors decreased I(Na) and quenched AA-induced channel activation, indicating that the effect of intracellular AA on Na(V) was possibly mediated through AA metabolites. In addition, the PGE2-induced activation of I(Na) was mimicked by cAMP and quenched by a PKA (protein kinase A) inhibitor, a G(s) inhibitor and EP (E-series of prostaglandin) receptor antagonists. The results of the present study suggest that extracellular AA modulates Na(V) channel activity in rat cerebellar GCs without metabolic conversion, whereas intracellular AA augments the I(Na) by PGE(2)-mediated activation of cAMP/PKA pathways. These observations may explain the dual character of AA in neuronal pathogenesis.

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“…A), which was significantly different from the results obtained without KN‐93 ( P < 0.05), suggesting that the Ca 2+ /CaM pathway is associated with the inhibitory effect of MT on the ELF‐EMF exposure–induced increase in I Na . We then tested the effect on ELF‐EMF exposure–induced increase in I Na by treatment of C 6 ‐ceramide, which increases Ca 2+ release through the ryanodine‐sensitive Ca 2+ receptor . Based on our results, C 6 ‐ceramide could mimic the effect of MT and decreased the ELF‐EMF‐induced inhibitory effect in I Na from 71.2 ± 8.0% to 16.8 ± 11.7% ( n = 11, Fig.…”

Section: Resultsmentioning

confidence: 92%

“…5B). In rat cerebellar GCs, intracellular Ca 2+ is mainly released by the ryanodinesensitive Ca 2+ receptor pathway [35]. Therefore, we used ruthenium A B Fig.…”

mentioning

confidence: 99%

Melatonin protects rat cerebellar granule cells against electromagnetic field‐induced increases in Na⁺ currents through intracellular Ca²⁺ release

Liu

Ren

Yang

et al. 2014

J Cellular Molecular Medi

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Although melatonin (MT) has been reported to protect cells against oxidative damage induced by electromagnetic radiation, few reports have addressed whether there are other protective mechanisms. Here, we investigated the effects of MT on extremely low-frequency electromagnetic field (ELF-EMF)-induced Nav activity in rat cerebellar granule cells (GCs). Exposing cerebellar GCs to ELF-EMF for 60 min. significantly increased the Nav current (INa) densities by 62.5%. MT (5 μM) inhibited the ELF-EMF-induced INa increase. This inhibitory effect of MT is mimicked by an MT2 receptor agonist and was eliminated by an MT2 receptor antagonist. The Nav channel steady-state activation curve was significantly shifted towards hyperpolarization by ELF-EMF stimulation but remained unchanged by MT in cerebellar GC that were either exposed or not exposed to ELF-EMF. ELF-EMF exposure significantly increased the intracellular levels of phosphorylated PKA in cerebellar GCs, and both MT and IIK-7 did not reduce the ELF-EMF-induced increase in phosphorylated PKA. The inhibitory effects of MT on ELF-EMF-induced Nav activity was greatly reduced by the calmodulin inhibitor KN93. Calcium imaging showed that MT did not increase the basal intracellular Ca2+ level, but it significantly elevated the intracellular Ca2+ level evoked by the high K+ stimulation in cerebellar GC that were either exposed or not exposed to ELF-EMF. In the presence of ruthenium red, a ryanodine-sensitive receptor blocker, the MT-induced increase in intracellular calcium levels was reduced. Our data show for the first time that MT protects against neuronal INa that result from ELF-EMF exposure through Ca2+ influx-induced Ca2+ release.

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PLC‐dependent intracellular Ca²⁺ release was associated with C₆‐ceramide‐induced inhibition of Na⁺ current in rat granule cells

Cited by 7 publications

References 52 publications

Exposure to Extremely Low-Frequency Electromagnetic Fields Modulates Na+ Currents in Rat Cerebellar Granule Cells through Increase of AA/PGE2 and EP Receptor-Mediated cAMP/PKA Pathway

Exposure to Extremely Low-Frequency Electromagnetic Fields Modulates Na+ Currents in Rat Cerebellar Granule Cells through Increase of AA/PGE2 and EP Receptor-Mediated cAMP/PKA Pathway

Arachidonic acid modulates Na+ currents by non-metabolic and metabolic pathways in rat cerebellar granule cells

Melatonin protects rat cerebellar granule cells against electromagnetic field‐induced increases in Na⁺ currents through intracellular Ca²⁺ release

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PLC‐dependent intracellular Ca2+ release was associated with C6‐ceramide‐induced inhibition of Na+ current in rat granule cells

Cited by 7 publications

References 52 publications

Exposure to Extremely Low-Frequency Electromagnetic Fields Modulates Na+ Currents in Rat Cerebellar Granule Cells through Increase of AA/PGE2 and EP Receptor-Mediated cAMP/PKA Pathway

Exposure to Extremely Low-Frequency Electromagnetic Fields Modulates Na+ Currents in Rat Cerebellar Granule Cells through Increase of AA/PGE2 and EP Receptor-Mediated cAMP/PKA Pathway

Arachidonic acid modulates Na+ currents by non-metabolic and metabolic pathways in rat cerebellar granule cells

Melatonin protects rat cerebellar granule cells against electromagnetic field‐induced increases in Na+ currents through intracellular Ca2+ release

Contact Info

Product

Resources

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PLC‐dependent intracellular Ca²⁺ release was associated with C₆‐ceramide‐induced inhibition of Na⁺ current in rat granule cells

Melatonin protects rat cerebellar granule cells against electromagnetic field‐induced increases in Na⁺ currents through intracellular Ca²⁺ release