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Mechanism of calcium gating in small-conductance calcium-activated potassium channels

Abstract

The slow afterhyperpolarization that follows an action potential is generated by the activation of small-conductance calcium-activated potassium channels (SK channels). The slow afterhyperpolarization limits the firing frequency of repetitive action potentials (spike-frequency adaption) and is essential for normal neurotransmission1,2,3. SK channels are voltage-independent and activated by submicromolar concentrations of intracellular calcium1. They are high-affinity calcium sensors that transduce fluctuations in intracellular calcium concentrations into changes in membrane potential. Here we study the mechanism of calcium gating and find that SK channels are not gated by calcium binding directly to the channel α-subunits. Instead, the functional SK channels are heteromeric complexes with calmodulin, which is constitutively associated with the α-subunits in a calcium-independent manner. Our data support a model in which calcium gating of SK channels is mediated by binding of calcium to calmodulin and subsequent conformational alterations in the channel protein.

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Figure 1: Ca2+ gating in SK channels.
Figure 2: Domains involved in Ca2+ gating.
Figure 3: Calmodulin interacts with SK channels in a yeast two-hybrid assay.
Figure 4: Calmodulin binds to SK channels.
Figure 5: Calmodulin mediates Ca2+ gating of SK channels.

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Acknowledgements

We thank T. Soderling and P. Ruppersberg for encouragement and fruitful conversations; K. Gibson for site-directed mutagenesis; D. Oliver for technical assistance; and L. Cordelia and E. Wiltshire for artwork and patience. This work was funded by NIH grants and a grant from ICAgen.

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Correspondence to J. P. Adelman.

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Xia, XM., Fakler, B., Rivard, A. et al. Mechanism of calcium gating in small-conductance calcium-activated potassium channels. Nature 395, 503–507 (1998). https://doi.org/10.1038/26758

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