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

Nature Neuroscience volume 9, pages 41–49 (2006)Cite this article

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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Figure 1: BK channels are made of pore-forming α- (slo) and modulatory β-subunits.
Figure 2: Ethanol at clinically relevant concentrations increases bslo T107V channel activity (NPo) after expression of these slo subunits in Xenopus oocytes.
Figure 3: The valine-to-threonine mutation in the slo S0–S1 loop significantly modifies BK channel responses to acute ethanol exposure.
Figure 4: In vitro treatment with alkaline phosphatase shifts wild-type bslo channels into a state that is readily activatable by ethanol, but does not modify bslo T107V channel responses to alcohol.
Figure 5: In vitro treatment with KN-93, a selective CaMKII inhibitor, shifted wild-type bslo channels into a state that is readily activatable by ethanol, but it does not modify bslo T107V channel responses to alcohol.
Figure 6: CaMKII increases wild-type bslo channel activity and switches channel responses to ethanol from activation to inhibition.
Figure 7: CaMKII phosphorylation of Thr107 progressively switches channel responses to ethanol.

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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, 38163, Tennessee, USA

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

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Correspondence to Alejandro M Dopico.

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Supplementary information

Supplementary Figure 1

Increasing the proportion of bslo T107V Y315V in the tetramer increases channel unitary conductance in a discrete manner. (PDF 79 kb)

Supplementary Note

CamKII and ethanol modify bslo currents by producing a parallel shift in the G/Gmax-V relationship. (PDF 66 kb)

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Liu, J., Asuncion-Chin, M., Liu, P. et al. CaM kinase II phosphorylation of slo Thr107 regulates activity and ethanol responses of BK channels. Nat Neurosci 9, 41–49 (2006). https://doi.org/10.1038/nn1602

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