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CaM kinase II phosphorylation of slo Thr107 regulates activity and ethanol responses of BK channels

Nature Neuroscience volume 9, pages 4149 (2006) | Download Citation

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Abstract

High-conductance, Ca2+-activated and voltage-gated (BK) channels set neuronal firing. They are almost universally activated by alcohol, leading to reduced neuronal excitability and neuropeptide release and to motor intoxication. However, several BK channels are inhibited by alcohol, and most other voltage-gated K+ channels are refractory to drug action. BK channels are homotetramers (encoded by Slo1) that possess a unique transmembrane segment (S0), leading to a cytosolic S0–S1 loop. We identified Thr107 of bovine slo (bslo) in this loop as a critical residue that determines BK channel responses to alcohol. In addition, the activity of Ca2+/calmodulin-dependent protein kinase II (CaMKII) in the cell controlled channel activity and alcohol modulation. Incremental CaMKII-mediated phosphorylation of Thr107 in the BK tetramer progressively increased channel activity and gradually switched the channel alcohol responses from robust activation to inhibition. Thus, CaMKII phosphorylation of slo Thr107 works as a 'molecular dimmer switch' that could mediate tolerance to alcohol, a form of neuronal plasticity.

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Acknowledgements

We thank S. Bahouth, S. Tavalin, J. Jaggar and D. Armbruster for critically reading the manuscript, and K. Malik for helpful discussion. This work was supported by the US National Institutes of Health (grants AA11560 and HL77424 to A.M.D.).

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  1. Department of Pharmacology, University of Tennessee Health Science Center, 874 Union Avenue, Memphis, Tennessee 38163, USA.

    • Jianxi Liu
    • , Maria Asuncion-Chin
    • , Pengchong Liu
    •  & Alejandro M Dopico

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The authors declare no competing financial interests.

Corresponding author

Correspondence to Alejandro M Dopico.

Supplementary information

PDF files

  1. 1.

    Supplementary Figure 1

    Increasing the proportion of bslo T107V Y315V in the tetramer increases channel unitary conductance in a discrete manner.

  2. 2.

    Supplementary Note

    CamKII and ethanol modify bslo currents by producing a parallel shift in the G/Gmax-V relationship.

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DOI

https://doi.org/10.1038/nn1602

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