2021

Kschonsak, M., Chua, H.C., Weidling, C. et al. Structural architecture of the human NALCN channelosome. Nature 603, 180–186 (2022). https://doi.org/10.1038/s41586-021-04313-5

Hathaichanok Impheng,Céline Lemmers,Malik Bouasse, Christian Legros,Narawut Pakaprot,Nathalie C. Guérineau,Philippe Lory,Arnaud Monteil. The sodium leak channel NALCN regulates cell excitability of pituitary endocrine cells. The FASEB Journal. 2021; 35:e21400. https://doi.org/10.1096/fj.202000841RR

Zhang D, Zhao W, Liu J, Ou M, Liang P, Li J, Chen Y, Liao D, Bai S, Shen J, Chen X, Huang H, Zhou C. Sodium leak channel contributes to neuronal sensitization in neuropathic pain. Prog Neurobiol. 2021 Mar 22:102041. doi: 10.1016/j.pneurobio.2021.102041. Epub ahead of print. PMID: 33766679.

Kasap M, Dwyer DS. Na⁺ leak-current channel (NALCN) at the junction of motor and neuropsychiatric symptoms in Parkinson’s disease. J Neural Transm (Vienna). 2021 May 7. doi: 10.1007/s00702-021-02348-6. Epub ahead of print. PMID: 33961117.

September 2020

Our understanding of the NALCN protein complex responsible for the CLIFAHDD
and IHPRF1&2 syndromes has reached new milestones over the last months.

Two recent studies (Ou et al, 2020; Kschonsak et al, 2020) just confirmed the initial
finding (Bouasse et al, 2019) that CLIFAHDD and IHPRF1 are due to mutations that
alter NALCN function in opposite ways, i.e. through a gain- or a loss-of-function,
respectively. Now, researchers must find ways to modulate directly the NALCN
function or counterbalance its deficiency. This challenge will undoubtedly benefit
from the elucidation of the 3-dimensional NALCN structure by three different groups
(Kschonsak et al, 2020; Zhang et al; Xie et al), and the identification of a lock that
will be a target of choice to find the right keys to close or open it.

The quest for NALCN inhibitors to treat patients with the CLIFAHDD syndrome is
particularly relevant since a study conducted in worms provided the first proof-of-concept that dystonia caused by a gain-of-function mutation of NALCN may be
corrected in vivo. Moreover, several studies already reported how NALCN function is
modulated by extracellular calcium (Lee et al, 2019; Chua et al, 2020), isoflurane
(e.g. a volatile anesthetic; Ou et al, 2020), and other chemical compounds (Hahn et
al, 2020).

The design of future drugs will build on the ground of these pioneer data.

Other studies reported novel mutations of NALCN in patients with the IHPRF1
syndromes (Ope et al, 2020), and a mouse model of the IHPRF2 syndrome linked to
UNC-80 dysfunction was developed as well as a mouse model expressing a “green”
NALCN protein, which unveiled that UNC-80 impacts on NALCN function by
disrupting its neuronal localization (Wie et al, 2020).

Unexpectedly, two other studies revealed that NALCN is also involved well beyond
CLIFAHDD and IHPRF1&2 syndromes, in cancer and in neuropathic pain
(Iamshanova et al; Zhang et al).

One may thus expect a growing interest for this
once neglected protein. Together with the ability of expressing NALCN in cultured
cells and the knowledge of its 3D structure, this will speed up the identification of
specific molecules to modulate its function, and the development of novel therapeutic
strategies for patients. It is now predictable that major advances will be
accomplished within the next years.

*Studies deposited to bioRxiv are not peer-reviewed ones.