New insights into the physiology and pathophysiology of the atypical sodium leak channel NALCN
Issued Date
2024-01-01
Resource Type
eISSN
15221210
Scopus ID
2-s2.0-85179123081
Pubmed ID
37615954
Journal Title
Physiological reviews
Volume
104
Issue
1
Start Page
399
End Page
472
Rights Holder(s)
SCOPUS
Bibliographic Citation
Physiological reviews Vol.104 No.1 (2024) , 399-472
Suggested Citation
Monteil A., Guérineau N.C., Gil-Nagel A., Parra-Diaz P., Lory P., Senatore A. New insights into the physiology and pathophysiology of the atypical sodium leak channel NALCN. Physiological reviews Vol.104 No.1 (2024) , 399-472. 472. doi:10.1152/physrev.00014.2022 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/91495
Title
New insights into the physiology and pathophysiology of the atypical sodium leak channel NALCN
Other Contributor(s)
Abstract
Cell excitability and its modulation by hormones and neurotransmitters involve the concerted action of a large repertoire of membrane proteins, especially ion channels. Unique complements of coexpressed ion channels are exquisitely balanced against each other in different excitable cell types, establishing distinct electrical properties that are tailored for diverse physiological contributions, and dysfunction of any component may induce a disease state. A crucial parameter controlling cell excitability is the resting membrane potential (RMP) set by extra- and intracellular concentrations of ions, mainly Na+, K+, and Cl-, and their passive permeation across the cell membrane through leak ion channels. Indeed, dysregulation of RMP causes significant effects on cellular excitability. This review describes the molecular and physiological properties of the Na+ leak channel NALCN, which associates with its accessory subunits UNC-79, UNC-80, and NLF-1/FAM155 to conduct depolarizing background Na+ currents in various excitable cell types, especially neurons. Studies of animal models clearly demonstrate that NALCN contributes to fundamental physiological processes in the nervous system including the control of respiratory rhythm, circadian rhythm, sleep, and locomotor behavior. Furthermore, dysfunction of NALCN and its subunits is associated with severe pathological states in humans. The critical involvement of NALCN in physiology is now well established, but its study has been hampered by the lack of specific drugs that can block or agonize NALCN currents in vitro and in vivo. Molecular tools and animal models are now available to accelerate our understanding of how NALCN contributes to key physiological functions and the development of novel therapies for NALCN channelopathies.