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• W2100300330 abstract "Large-conductance calcium-activated potassium channels (BK) are potent negative regulators of excitability in neurons and muscle, and increasing BK current is a novel therapeutic strategy for neuro- and cardioprotection, disorders of smooth muscle hyperactivity, and several psychiatric diseases. However, in some neurons, enhanced BK current is linked with seizures and paradoxical increases in excitability, potentially complicating the clinical use of agonists. The mechanisms that switch BK influence from inhibitory to excitatory are not well defined. Here we investigate this dichotomy using a gain-of-function subunit (BK R207Q ) to enhance BK currents. Heterologous expression of BK R207Q generated currents that activated at physiologically relevant voltages in lower intracellular Ca 2+ , activated faster, and deactivated slower than wild-type currents. We then used BK R207Q expression to broadly augment endogenous BK currents in vivo, generating a transgenic mouse from a circadian clock-controlled Period1 gene fragment ( Tg-BK R207Q ). The specific impact on excitability was assessed in neurons of the suprachiasmatic nucleus (SCN) in the hypothalamus, a cell type where BK currents regulate spontaneous firing under distinct day and night conditions that are defined by different complements of ionic currents. In the SCN, Tg-BK R207Q expression converted the endogenous BK current to fast-activating, while maintaining similar current-voltage properties between day and night. Alteration of BK currents in Tg-BK R207Q SCN neurons increased firing at night but decreased firing during the day, demonstrating that BK currents generate bidirectional effects on neuronal firing under distinct conditions." @default.
• W2100300330 created "2016-06-24" @default.
• W2100300330 creator A5039458992 @default.
• W2100300330 creator A5090679062 @default.
• W2100300330 date "2012-10-29" @default.
• W2100300330 modified "2023-10-02" @default.
• W2100300330 title "Genetic activation of BK currents in vivo generates bidirectional effects on neuronal excitability" @default.
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• W2100300330 doi "https://doi.org/10.1073/pnas.1205573109" @default.
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