IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-43475-w.html
   My bibliography  Save this article

Epilepsy-linked kinase CDKL5 phosphorylates voltage-gated calcium channel Cav2.3, altering inactivation kinetics and neuronal excitability

Author

Listed:
  • Marisol Sampedro-Castañeda

    (The Francis Crick Institute)

  • Lucas L. Baltussen

    (The Francis Crick Institute
    Laboratory for the Research of Neurodegenerative Diseases (VIB-KU Leuven), Department of Neurosciences)

  • André T. Lopes

    (The Francis Crick Institute)

  • Yichen Qiu

    (UCL Queen Square Institute of Neurology, Queen Square House)

  • Liina Sirvio

    (The Francis Crick Institute)

  • Simeon R. Mihaylov

    (The Francis Crick Institute)

  • Suzanne Claxton

    (The Francis Crick Institute)

  • Jill C. Richardson

    (MSD Research Laboratories)

  • Gabriele Lignani

    (UCL Queen Square Institute of Neurology, Queen Square House)

  • Sila K. Ultanir

    (The Francis Crick Institute)

Abstract

Developmental and epileptic encephalopathies (DEEs) are a group of rare childhood disorders characterized by severe epilepsy and cognitive deficits. Numerous DEE genes have been discovered thanks to advances in genomic diagnosis, yet putative molecular links between these disorders are unknown. CDKL5 deficiency disorder (CDD, DEE2), one of the most common genetic epilepsies, is caused by loss-of-function mutations in the brain-enriched kinase CDKL5. To elucidate CDKL5 function, we looked for CDKL5 substrates using a SILAC-based phosphoproteomic screen. We identified the voltage-gated Ca2+ channel Cav2.3 (encoded by CACNA1E) as a physiological target of CDKL5 in mice and humans. Recombinant channel electrophysiology and interdisciplinary characterization of Cav2.3 phosphomutant mice revealed that loss of Cav2.3 phosphorylation leads to channel gain-of-function via slower inactivation and enhanced cholinergic stimulation, resulting in increased neuronal excitability. Our results thus show that CDD is partly a channelopathy. The properties of unphosphorylated Cav2.3 closely resemble those described for CACNA1E gain-of-function mutations causing DEE69, a disorder sharing clinical features with CDD. We show that these two single-gene diseases are mechanistically related and could be ameliorated with Cav2.3 inhibitors.

Suggested Citation

  • Marisol Sampedro-Castañeda & Lucas L. Baltussen & André T. Lopes & Yichen Qiu & Liina Sirvio & Simeon R. Mihaylov & Suzanne Claxton & Jill C. Richardson & Gabriele Lignani & Sila K. Ultanir, 2023. "Epilepsy-linked kinase CDKL5 phosphorylates voltage-gated calcium channel Cav2.3, altering inactivation kinetics and neuronal excitability," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43475-w
    DOI: 10.1038/s41467-023-43475-w
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-43475-w
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-023-43475-w?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Julia Benkert & Simon Hess & Shoumik Roy & Dayne Beccano-Kelly & Nicole Wiederspohn & Johanna Duda & Carsten Simons & Komal Patil & Aisylu Gaifullina & Nadja Mannal & Elena Dragicevic & Desirée Spaich, 2019. "Cav2.3 channels contribute to dopaminergic neuron loss in a model of Parkinson’s disease," Nature Communications, Nature, vol. 10(1), pages 1-11, December.
    2. Sheng Tang & Barbara Terzic & I-Ting Judy Wang & Nicolas Sarmiento & Katherine Sizov & Yue Cui & Hajime Takano & Eric D. Marsh & Zhaolan Zhou & Douglas A. Coulter, 2019. "Altered NMDAR signaling underlies autistic-like features in mouse models of CDKL5 deficiency disorder," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Yiwei Gao & Shuai Xu & Xiaoli Cui & Hao Xu & Yunlong Qiu & Yiqing Wei & Yanli Dong & Boling Zhu & Chao Peng & Shiqi Liu & Xuejun Cai Zhang & Jianyuan Sun & Zhuo Huang & Yan Zhao, 2023. "Molecular insights into the gating mechanisms of voltage-gated calcium channel CaV2.3," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    2. Xia Yao & Yan Wang & Zhifei Wang & Xiao Fan & Di Wu & Jian Huang & Alexander Mueller & Sarah Gao & Miaohui Hu & Carol V. Robinson & Yong Yu & Shuai Gao & Nieng Yan, 2022. "Structures of the R-type human Cav2.3 channel reveal conformational crosstalk of the intracellular segments," Nature Communications, Nature, vol. 13(1), pages 1-11, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43475-w. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.