Dataset Information

Nuclear BK channels regulate gene expression via the control of nuclear calcium signaling.

ABSTRACT: Ion channels are essential for the regulation of neuronal functions. The significance of plasma membrane, mitochondrial, endoplasmic reticulum and lysosomal ion channels in the regulation of Ca(2+) is well established. In contrast, surprisingly little is known about the function of ion channels on the nuclear envelope (NE). Here we demonstrate the presence of functional large-conductance, calcium-activated potassium channels (BK channels) on the NE of rodent hippocampal neurons. Functionally, blockade of nuclear BK channels (nBK channels) induces NE-derived Ca(2+) release, nucleoplasmic Ca(2+) elevation and cyclic AMP response element binding protein (CREB)-dependent transcription. More importantly, blockade of nBK channels regulates nuclear Ca(2+)-sensitive gene expression and promotes dendritic arborization in a nuclear Ca(2+)-dependent manner. These results suggest that the nBK channel functions as a molecular link between neuronal activity and nuclear Ca(2+) to convey signals from synapse to nucleus and is a new modulator, operating at the NE, of synaptic activity-dependent neuronal functions.

SUBMITTER: Li B

PROVIDER: S-EPMC4115017 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Nuclear BK channels regulate gene expression via the control of nuclear calcium signaling.

Li Boxing B Jie Wei W Huang Lianyan L Wei Peng P Li Shuji S Luo Zhengyi Z Friedman Allyson K AK Meredith Andrea L AL Han Ming-Hu MH Zhu Xin-Hong XH Gao Tian-Ming TM

Nature neuroscience 20140622 8

Ion channels are essential for the regulation of neuronal functions. The significance of plasma membrane, mitochondrial, endoplasmic reticulum and lysosomal ion channels in the regulation of Ca(2+) is well established. In contrast, surprisingly little is known about the function of ion channels on the nuclear envelope (NE). Here we demonstrate the presence of functional large-conductance, calcium-activated potassium channels (BK channels) on the NE of rodent hippocampal neurons. Functionally, bl ...[more]

PMID: 24952642

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Project description:It has been suggested that drug tolerance represents a form of learning and memory, but this has not been experimentally established at the molecular level. We show that a component of alcohol molecular tolerance (channel internalization) from rat hippocampal neurons requires protein synthesis, in common with other forms of learning and memory. We identify ?-catenin as a primary necessary protein. Alcohol increases ?-catenin, and blocking accumulation of ?-catenin blocks alcohol-induced internalization in these neurons. In transfected HEK293 cells, suppression of Wnt/?-catenin signaling blocks ethanol-induced internalization. Conversely, activation of Wnt/?-catenin reduces BK current density. A point mutation in a putative glycogen synthase kinase phosophorylation site within the S10 region of BK blocks internalization, suggesting that Wnt/?-catenin directly regulates alcohol-induced BK internalization via glycogen synthase kinase phosphorylation. These findings establish de novo protein synthesis and Wnt/?-catenin signaling as critical in mediating a persistent form of BK molecular alcohol tolerance establishing a commonality with other forms of long-term plasticity.Alcohol tolerance is a key step toward escalating alcohol consumption and subsequent dependence. Our research aims to make significant contributions toward novel, therapeutic approaches to prevent and treat alcohol misuse by understanding the molecular mechanisms of alcohol tolerance. In our current study, we identify the role of a key regulatory pathway in alcohol-induced persistent molecular changes within the hippocampus. The canonical Wnt/?-catenin pathway regulates BK channel surface expression in a protein synthesis-dependent manner reminiscent of other forms of long-term hippocampal neuronal adaptations. This unique insight opens the possibility of using clinically tested drugs, targeting the Wnt/?-catenin pathway, for the novel use of preventing and treating alcohol dependency.

Dataset Information

Nuclear BK channels regulate gene expression via the control of nuclear calcium signaling.

Publications

Nuclear BK channels regulate gene expression via the control of nuclear calcium signaling.

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