The regulation of the small-conductance calcium-activated potassium current and the mechanisms of sex dimorphism in J wave syndrome

Mu, Chunlai; Fei, Yudong; Chen, Tai-Zhong; Li, Yi‐Gang; Chen, Peng‐Sheng

doi:10.1007/s00424-020-02500-3

Cited by 7 publications

(5 citation statements)

References 114 publications

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“…Whether the same mechanism also holds true 3 Neural Plasticity in female mice remains to be determined, but if it were, estrogen-mediated PKA activation could account for the differences in LTP between male and female AS mice. Along this line, to the best of our knowledge, sex differences in the expression and regulation of SK2 channels in the CNS remain unsettled, although sexual dimorphism has been reported in cardiac SK channel activation and regulation [50]. Additionally, SK2 channels have been shown to influ-ence neuronal intrinsic plasticity through regulation of membrane excitability [51,52].…”

Section: Discussionmentioning

confidence: 99%

Lack of UBE3A-Mediated Regulation of Synaptic SK2 Channels Contributes to Learning and Memory Impairment in the Female Mouse Model of Angelman Syndrome

et al. 2022

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Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by severe developmental delay, motor impairment, language and cognition deficits, and often with increased seizure activity. AS is caused by deficiency of UBE3A, which is both an E3 ligase and a cofactor for transcriptional regulation. We previously showed that the small conductance potassium channel protein SK2 is a UBE3A substrate, and that increased synaptic SK2 levels contribute to impairments in synaptic plasticity and fear-conditioning memory, as inhibition of SK2 channels significantly improved both synaptic plasticity and fear memory in male AS mice. In the present study, we investigated UBE3a-mediated regulation of synaptic plasticity and fear-conditioning in female AS mice. Results from both western blot and immunofluorescence analyses showed that synaptic SK2 levels were significantly increased in hippocampus of female AS mice, as compared to wild-type (WT) littermates. Like in male AS mice, long-term potentiation (LTP) was significantly reduced while long-term depression (LTD) was enhanced at hippocampal CA3-CA1 synapses of female AS mice, as compared to female WT mice. Both alterations were significantly reduced by treatment with the SK2 inhibitor, apamin. The shunting effect of SK2 channels on NMDA receptor was significantly larger in female AS mice as compared to female WT mice. Female AS mice also showed impairment in both contextual and tone memory recall, and this impairment was significantly reduced by apamin treatment. Our results indicate that like male AS mice, female AS mice showed significant impairment in both synaptic plasticity and fear-conditioning memory due to increased levels of synaptic SK2 channels. Any therapeutic strategy to reduce SK2-mediated inhibition of NMDAR should be beneficial to both male and female patients.

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Section: Discussionmentioning

confidence: 99%

Lack of UBE3A-Mediated Regulation of Synaptic SK2 Channels Contributes to Learning and Memory Impairment in the Female Mouse Model of Angelman Syndrome

et al. 2022

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“…We next studied which channels among Ca 2+ -activated K + channels are involved. Paxillin, a BK channel inhibitor (González et al, 2012) and UCL 1684 or apamin, SK channel inhibitors (Chen et al, 2021; Strøbæk et al, 2000) did not significantly affect IL-1β release by LP ( Figure 5-figure supplement 1D ). In contrast, TRAM-34, a specific IKCa1 (KCa3.1) channel inhibitor (Agarwal et al, 2014; Wulff et al, 2000), significantly decreased IL-1β release by LP ( Figure 5-figure supplement 1C and D ), suggesting involvement of KCa3.1.…”

Section: Resultsmentioning

confidence: 98%

ER-to-lysosome Ca²⁺refilling followed by K⁺efflux-coupled store-operated Ca²⁺entry in inflammasome activation and metabolic inflammation

Kang

Choi

Kim

et al. 2023

Preprint

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We studied lysosomal Ca2+in inflammasome. LPS+palmitic acid (PA) decreased lysosomal Ca2+([Ca2+]Lys) and increased [Ca2+]ithrough mitochondrial ROS, which was suppressed inTrpm2-KO macrophages. Inflammasome activation and metabolic inflammation in adipose tissue of high-fat diet (HFD)-fed mice were ameliorated byTrpm2KO. ER→lysosome Ca2+refilling occurred after lysosomal Ca2+release whose blockade attenuated LPS+PA-induced inflammasome. Subsequently, store-operated Ca2+entry (SOCE) was activated whose inhibition suppressed inflammasome. SOCE was coupled with K+efflux whose inhibition reduced ER Ca2+content ([Ca2+]ER) and impaired [Ca2+]Lysrecovery. LPS+PA activated KCa3.1 channel, a Ca2+-activated K+channel. Inhibitors of KCa3.1 channel orKcnn4KO reduced [Ca2+]ER, [Ca2+]iincrease or inflammasome by LPS+PA, and ameliorated HFD-induced inflammasome or metabolic inflammation. Lysosomal Ca2+release induced delayed JNK and ASC phosphorylation through CAMKII-ASK1. These results suggest a novel role of lysosomal Ca2+release sustained by ER→lysosome Ca2+refilling and K+efflux through KCa3.1 channel in inflammasome and metabolic inflammation.

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“…We next studied which channels among Ca 2+ -activated K + channels are involved. Paxillin, a BK channel inhibitor (González et al, 2012 ) and UCL 1684 or apamin, SK channel inhibitors (Chen et al, 2021 ;Strøbaek et al, 2000 ) did not significantly affect IL-1β release by LP (Figure 5-figure supplement 1D ). In contrast, TRAM-34, a specific IKCa1 (KCa3.1) channel inhibitor (Agarwal et al, 2014 ;Wulff et al, 2000 ), significantly decreased IL-1β release by LP (Figure 5…”

Section: Coupling Of K + Efflux and Ca 2+ Influx In Inflammasomementioning

confidence: 95%

ER-to-lysosome Ca2+ refilling followed by K+ efflux-coupled store-operated Ca2+ entry in inflammasome activation and metabolic inflammation

Kang,

Choi,

Kim

et al. 2024

Preprint

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We studied lysosomal Ca2+ in inflammasome. LPS+palmitic acid (PA) decreased lysosomal Ca2+ ([Ca2+]Lys) and increased [Ca2+]i through mitochondrial ROS, which was suppressed in Trpm2-KO macrophages. Inflammasome activation and metabolic inflammation in adipose tissue of high-fat diet (HFD)-fed mice were ameliorated by Trpm2 KO. ER→lysosome Ca2+ refilling occurred after lysosomal Ca2+ release whose blockade attenuated LPS+PA-induced inflammasome. Subsequently, store-operated Ca2+entry (SOCE) was activated whose inhibition suppressed inflammasome. SOCE was coupled with K+ efflux whose inhibition reduced ER Ca2+ content ([Ca2+]ER) and impaired [Ca2+]Lys recovery. LPS+PA activated KCa3.1 channel, a Ca2+-activated K+ channel. Inhibitors of KCa3.1 channel or Kcnn4 KO reduced [Ca2+]ER, [Ca2+]i increase or inflammasome by LPS+PA, and ameliorated HFD-induced inflammasome or metabolic inflammation. Lysosomal Ca2+ release induced delayed JNK and ASC phosphorylation through CAMKII-ASK1. These results suggest a novel role of lysosomal Ca2+ release sustained by ER→lysosome Ca2+ refilling and K+ efflux through KCa3.1 channel in inflammasome and metabolic inflammation.

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The regulation of the small-conductance calcium-activated potassium current and the mechanisms of sex dimorphism in J wave syndrome

Cited by 7 publications

References 114 publications

Lack of UBE3A-Mediated Regulation of Synaptic SK2 Channels Contributes to Learning and Memory Impairment in the Female Mouse Model of Angelman Syndrome

Lack of UBE3A-Mediated Regulation of Synaptic SK2 Channels Contributes to Learning and Memory Impairment in the Female Mouse Model of Angelman Syndrome

ER-to-lysosome Ca²⁺refilling followed by K⁺efflux-coupled store-operated Ca²⁺entry in inflammasome activation and metabolic inflammation

ER-to-lysosome Ca2+ refilling followed by K+ efflux-coupled store-operated Ca2+ entry in inflammasome activation and metabolic inflammation

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The regulation of the small-conductance calcium-activated potassium current and the mechanisms of sex dimorphism in J wave syndrome

Cited by 7 publications

References 114 publications

Lack of UBE3A-Mediated Regulation of Synaptic SK2 Channels Contributes to Learning and Memory Impairment in the Female Mouse Model of Angelman Syndrome

Lack of UBE3A-Mediated Regulation of Synaptic SK2 Channels Contributes to Learning and Memory Impairment in the Female Mouse Model of Angelman Syndrome

ER-to-lysosome Ca2+refilling followed by K+efflux-coupled store-operated Ca2+entry in inflammasome activation and metabolic inflammation

ER-to-lysosome Ca2+ refilling followed by K+ efflux-coupled store-operated Ca2+ entry in inflammasome activation and metabolic inflammation

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ER-to-lysosome Ca²⁺refilling followed by K⁺efflux-coupled store-operated Ca²⁺entry in inflammasome activation and metabolic inflammation