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- W2026243136 abstract "Na+-activated potassium (KNa) channels encoded by the Slack and Slick genes contribute to neuronal adaptation during sustained stimulation and regulate the accuracy of timing of action potentials. Activation of protein kinase C (PKC) increases the amplitude of Slack-B currents and slows their rate of activation. Mutations in Slack channels which result in constitutive channel activation by mimicking phosphorylation cause malignant migrating partial seizures of infancy (MMPSI), a rare epileptic encephalopathy of infancy that combines pharmacoresistant seizures with severe developmental delay. Slack protein is known to interact with a variety of cytoplasmic signaling molecules. Using resonance wavelength grating optical biosensors (the SRU Biosciences BIND system), we have determined that direct pharmacological activation of Slack channels by bithionol produces a sustained decrease in mass distribution close to the plasma membrane, and that phosphorylation of Slack channels mimics this decrease in mass. The very C-terminal domain of Slack has been previously shown necessary for channel-protein interactions, and deletion of this region abolished the observed signal. To determine which proteins or signaling molecules are translocating from the plasma membrane upon channel activation, an RNAi screen against probable channel binding partners was performed, and the Protein Phosphatase 1 (PP1) targeting protein Phactr1 was found to be necessary for this decrease in mass. We hypothesize that activation of Slack by either bithionol or phosphorylation leads to the dissociation of Phactr1 with PP1 from the channel complex, allowing the Slack channel to remain in its phosphorylated and active state. Activation of PKC does not result in a decrease in mass in the human MMPSI mutants, possibly linking channel excitability to downstream signaling mechanisms which may result in developmental delay." @default.
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- W2026243136 date "2013-01-01" @default.
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- W2026243136 title "Use of Resonance-Wavelength Grating Optical Biosensors to Detect Channel-Protein Interaction in Slack KNa Channels" @default.
- W2026243136 doi "https://doi.org/10.1016/j.bpj.2012.11.750" @default.
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