Abstract
One of the largest components of the delayed outward current that is active under physiological conditions in many mammalian neurons, such as medium spiny neurons of the striatum and tufted-mitral cells of the olfactory bulb, has gone unnoticed and is the result of a Na+-activated K+ current. Previous studies of K+ currents in mammalian neurons may have overlooked this large outward component because the sodium channel blocker tetrodotoxin (TTX) is typically used in such studies. We found that TTX also eliminated this delayed outward component in rat neurons as a secondary consequence. Unexpectedly, we found that the activity of a persistent inward sodium current (persistent INa) is highly effective at activating this large Na+-dependent (TTX sensitive) delayed outward current. Using siRNA techniques, we identified SLO2.2 channels as being carriers of this delayed outward current. These findings have far reaching implications for many aspects of cellular and systems neuroscience, as well as clinical neurology and pharmacology.
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Acknowledgements
We thank T. Hoshi and M. Nonet for their kind suggestions regarding the manuscript and F. Sigworth and L. Kaczmarek for the Slack-HEK cell line that we used in the control experiments. We also thank S. Harmon for his kind technical help and C. Santi and A. Butler for helpful comments. This work was supported by US National Institutes of Health grants R24 RR017342 and R01 GM067154.
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G.B. and T.A.H. undertook the major electrophysiological experiments and analysis of MSNs and tufted-mitral cells. A.W. and P.R. aided these studies and undertook control experiments. Y.-J.I.J. and K.O. conducted immunocytochemical studies and western blotting experiments, and also supported dissections and preparation of cell cultures. L.S. designed and supervised the study and wrote the paper, all in close consultation with G.B. and T.A.H.
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Budelli, G., Hage, T., Wei, A. et al. Na+-activated K+ channels express a large delayed outward current in neurons during normal physiology. Nat Neurosci 12, 745–750 (2009). https://doi.org/10.1038/nn.2313
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DOI: https://doi.org/10.1038/nn.2313
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