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

Citation
Wie, J., et al. “Intellectual Disability-Associated Unc80 Mutations Reveal Inter-Subunit Interaction And Dendritic Function Of The Nalcn Channel Complex.”. Nature Communications, p. 3351.
Center University of Pennsylvania
Author Jinhong Wie, Apoorva Bharthur, Morgan Wolfgang, Vinodh Narayanan, Keri Ramsey, C4RCD Research Group, Kimberly Aranda, Qi Zhang, Yandong Zhou, Dejian Ren
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.

Year of Publication
2020
Journal
Nature communications
Volume
11
Issue
1
Number of Pages
3351
Date Published
07/2020
ISSN Number
2041-1723
DOI
10.1038/s41467-020-17105-8
Alternate Journal
Nat Commun
PMID
32620897