An improved electrophysiological cellular assay to unlock the pharmacological modulation of the NALCN channelosome
Issued Date
2026-06-01
Resource Type
ISSN
07533322
eISSN
19506007
Scopus ID
2-s2.0-105037317433
Journal Title
Biomedicine and Pharmacotherapy
Volume
199
Rights Holder(s)
SCOPUS
Bibliographic Citation
Biomedicine and Pharmacotherapy Vol.199 (2026)
Suggested Citation
Thongsepee N., Typou A., Baudat R., Tanner J.A., Del Pino I., Dwyer D.S., Lory P., Monteil A. An improved electrophysiological cellular assay to unlock the pharmacological modulation of the NALCN channelosome. Biomedicine and Pharmacotherapy Vol.199 (2026). doi:10.1016/j.biopha.2026.119458 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/116570
Title
An improved electrophysiological cellular assay to unlock the pharmacological modulation of the NALCN channelosome
Corresponding Author(s)
Other Contributor(s)
Abstract
The sodium leak channel non-selective (NALCN) is a key regulator of resting membrane potential and cellular excitability in neurons and endocrine cells. Gain-of-function de novo pathogenic variants in NALCN cause severe neurodevelopmental disorders with a broad and heterogeneous clinical spectrum. Partial inhibition of NALCN has been proposed as a therapeutic strategy; however, progress has been limited by the absence of selective pharmacological modulators. This gap largely reflects the lack of a robust heterologous expression system suitable for high-throughput screening, as functional NALCN requires multiple ancillary subunits and its constitutive expression is toxic in commonly used cell lines such as HEK293. To address these challenges, we developed a multitransposon-based approach to generate inducible HEK293 cell lines that stably express the complete NALCN channelosome, including wild-type and disease-associated variants. We further demonstrate that NALCN current expression is cell cycle–dependent, enabling the definition of optimized conditions for consistent and reproducible electrophysiological recordings. Using these cell lines, we conducted a systematic pharmacological characterization of the NALCN channelosome by patch-clamp electrophysiology and identified several candidate modulators that are currently under evaluation. Notably, we revisited NALCN modulation by N -benzhydryl quinuclidine compounds and found that these compounds can restore locomotor phenotypes in an animal model of NALCN gain-of-function. Together, this work establishes a foundational platform for the discovery of NALCN-targeting compounds and opens new therapeutic avenues not only for NALCN-associated neurodevelopmental diseases, but also potentially for psychiatric disorders, chronic pain, and cancer.