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Intellectual disability-associated UNC80 mutations reveal inter-subunit interaction and dendritic function of the NALCN channel complex

Author

Listed:
  • Jinhong Wie

    (University of Pennsylvania)

  • Apoorva Bharthur

    (University of Pennsylvania)

  • Morgan Wolfgang

    (Translational Genomics Research Institute)

  • Vinodh Narayanan

    (Translational Genomics Research Institute)

  • Keri Ramsey

    (Translational Genomics Research Institute)

  • Kimberly Aranda

    (University of Pennsylvania)

  • Qi Zhang

    (University of Pennsylvania)

  • Yandong Zhou

    (University of Pennsylvania
    Pennsylvania State University College of Medicine)

  • Dejian Ren

    (University of Pennsylvania)

Abstract

The sodium-leak channel NALCN forms a subthreshold sodium conductance that controls the resting membrane potentials of neurons. The auxiliary subunits of the channel and their functions in mammals are largely unknown. In this study, we demonstrate that two large proteins UNC80 and UNC79 are subunits of the NALCN complex. UNC80 knockout mice are neonatal lethal. The C-terminus of UNC80 contains a domain that interacts with UNC79 and overcomes a soma-retention signal to achieve dendritic localization. UNC80 lacking this domain, as found in human patients, still supports whole-cell NALCN currents but lacks dendritic localization. Our results establish the subunit composition of the NALCN complex, uncover the inter-subunit interaction domains, reveal the functional significance of regulation of dendritic membrane potential by the sodium-leak channel complex, and provide evidence supporting that genetic variations found in individuals with intellectual disability are the causes for the phenotype observed in patients.

Suggested Citation

  • Jinhong Wie & Apoorva Bharthur & Morgan Wolfgang & Vinodh Narayanan & Keri Ramsey & Kimberly Aranda & Qi Zhang & Yandong Zhou & Dejian Ren, 2020. "Intellectual disability-associated UNC80 mutations reveal inter-subunit interaction and dendritic function of the NALCN channel complex," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17105-8
    DOI: 10.1038/s41467-020-17105-8
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    Cited by:

    1. Winston H. Cuddleston & Junhao Li & Xuanjia Fan & Alexey Kozenkov & Matthew Lalli & Shahrukh Khalique & Stella Dracheva & Eran A. Mukamel & Michael S. Breen, 2022. "Cellular and genetic drivers of RNA editing variation in the human brain," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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