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Calmodulin kinase determines calcium-dependent facilitation of L-type calcium channels

Nature Cell Biology volume 2, pages 173–177 (2000)Cite this article

A Retraction to this article was published on 27 March 2015

Abstract

A dynamic positive feedback mechanism, known as ‘facilitation’, augments L-type calcium-ion currents (ICa) in response to increased intracellular Ca2+ concentrations. The Ca2+-binding protein calmodulin (CaM) has been implicated in facilitation, but the single-channel signature and the signalling events underlying Ca2+/CaM-dependent facilitation are unknown. Here we show that the Ca2+/CaM-dependent protein kinase II (CaMK) is necessary and possibly sufficient for ICa facilitation. CaMK induces a channel-gating mode that is characterized by frequent, long openings of L-type Ca2+ channels. We conclude that CaMK-mediated phosphorylation is an essential signalling event in triggering Ca2+/CaM-dependent ICa facilitation.

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Figure 1: Paired depolarizing pulses (–80 mV to +10 mV at 0.5 Hz) lead to Ca2+-dependent facilitation of whole-cell ICa.
Figure 2: Constitutively active CaMK causes prolonged openings of single L-type Ca2+ channels in excised inside-out patches.
Figure 3: Quantification of the open times of single L-type Ca2+ channels.
Figure 4: CaMK favours a single, high-open-probability mode of gating of L-type Ca2+ channels, characterized by prolonged channel openings.

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Acknowledgements

This work was supported by grants from the NIH (grants NHLBI, HL03727 and HL62494 to M.E.A.) and the American Heart Association (to M.E.A. and R.J.C.). J.R.B. is an Established Investigator of the American Heart Association. We thank M. Bass for technical assistance, and D. Roden and A. George for helpful criticisms and suggestions.

Correspondence and requests for materials should be addressed to M.E.A.

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Authors and Affiliations

  1. Department of Anesthesiology, Vanderbilt University, Nashville, 37232, Tennessee, USA

    Igor Dzhura & Jeffrey R. Balser

  2. Department of Internal Medicine, Vanderbilt University, Nashville, 37232, Tennessee, USA

    Yuejin Wu & Mark E. Anderson

  3. Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, 37232, Tennessee, USA

    Roger J. Colbran

  4. Department of Pharmacology, Vanderbilt University, Nashville, 37232, Tennessee, USA

    Jeffrey R. Balser & Mark E. Anderson

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Correspondence to Mark E. Anderson.

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Dzhura, I., Wu, Y., Colbran, R. et al. Calmodulin kinase determines calcium-dependent facilitation of L-type calcium channels. Nat Cell Biol 2, 173–177 (2000). https://doi.org/10.1038/35004052

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