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Regulation of neuronal activity by Cav3-Kv4 channel signaling complexes

Nature Neuroscience volume 13, pages 333–337 (2010)Cite this article

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Abstract

Kv4 low voltage–activated A-type potassium channels are widely expressed in excitable cells, where they control action potential firing, dendritic activity and synaptic integration. Kv4 channels exist as a complex that includes K+ channel–interacting proteins (KChIPs), which contain calcium-binding domains and therefore have the potential to confer calcium dependence on the Kv4 channel. We found that T-type calcium channels and Kv4 channels form a signaling complex in rat that efficiently couples calcium influx to KChIP3 to modulate Kv4 function. This interaction was critical for allowing Kv4 channels to function in the subthreshold membrane potential range to regulate neuronal firing properties. The widespread expression of these channels and accessory proteins indicates that the Cav3-Kv4 signaling complex is important for the function of a wide range of electrically excitable cells.

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Figure 1: A-type channels are regulated by calcium influx through T-type channels in cerebellar stellate cells.
Figure 2: Cav3 calcium channels are coupled to the Kv4 potassium channel complex.
Figure 3: Cav3-mediated calcium influx modulates Kv4 channel inactivation when coexpressed in tsA-201 cells.
Figure 4: KChIP3 proteins act as a calcium sensor in stellate cells to modulate IA window current and the gain of spike firing.

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Acknowledgements

We gratefully acknowledge J. McRory and M.L. Molineux for early contributions to protein analysis, H. Jerng and P. Pfaffinger for access to DPLP cDNA clones, and M. Kruskic and L. Chen for expert technical assistance. This work was supported by a grant from Canadian Institutes of Health Research (R.W.T. and G.W.Z.) and studentship support through an Achievers in Medical Sciences and T. Chen Fong Award (D.A.), Alberta Heritage Foundation for Medical Research (AHFMR) (W.H.M., R.R. and J.D.T.E.), Canadian Institutes of Health Research (W.H.M.), National Sciences and Engineering Research Council (R.R.), and an AHFMR Postdoctoral Fellowship (M.I.). R.W.T. is an AHFMR Scientist and G.W.Z. is an AHFMR Scientist and Canada Research Chair.

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Authors and Affiliations

  1. Departments of Physiology & Pharmacology and Cell Biology & Anatomy, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada

    Dustin Anderson, W Hamish Mehaffey, Mircea Iftinca, Renata Rehak, Jordan D T Engbers, Shahid Hameed, Gerald W Zamponi & Ray W Turner

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Contributions

R.W.T. and G.W.Z. designed the study. D.A., M.I., J.D.T.E., H.W.M., S.H. and R.R. performed the experiments and analyzed the data. D.A., H.W.M., R.W.T. and G.W.Z. wrote the manuscript.

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Correspondence to Ray W Turner.

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Anderson, D., Mehaffey, W., Iftinca, M. et al. Regulation of neuronal activity by Cav3-Kv4 channel signaling complexes. Nat Neurosci 13, 333–337 (2010). https://doi.org/10.1038/nn.2493

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