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University of Pennsylvania

Nat. Commun., Published: 03 July 2020, 11, Article number: 3351 (2020) | https://doi.org/10.1038/s41467-020-17105-8 Intellectual disability-associated UNC80 mutations reveal inter-subunit interaction and dendritic function of the NALCN channel complex

Jinhong Wie^1,#, Apoorva Bharthur¹, Morgan Wolfgang², Vinodh Narayanan², Keri Ramsey², C4RCD Research Group^*, Kimberly Aranda¹, Qi Zhang¹, Yandong Zhou^1,3 & Dejian Ren^1,#

¹Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
²Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, AZ 85012, USA.
³Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.

^#Corresponding author

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.

논문정보

형식Research article
게재일2020년 07월 (BRIC 등록일 2020-07-10)
연구진국외 연구진
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