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2021

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. | 1 of 17https://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.


References:
Chua HC, Wulf M, Weidling C, Rasmussen LP, Pless SA. The NALCN channel complex is voltage
sensitive and directly modulated by extracellular calcium. Sci Adv. 2020 Apr 24
;6(17):eaaz3154. doi:
10.1126/sciadv.aaz3154.


Hahn S, Kim SW, Um KB, Kim HJ, Park MK. N-benzhydryl quinuclidine compounds are a potent and
Src kinase-independent inhibitor of NALCN channel
s
. Br J Pharmacol. 2020 Aug;177(16):3795-3810.
doi: 10.1111/bph.15104.

Oksana Iamshanova, Dmitri Gordienko, Antoine Folcher, Alexandre Bokhobza, George Shapovalov,
Pascal Mariot, Laurent Allart, Emilie Desruelles, Corentin Spriet, Raquel Diez, Thibauld Oullier,
Séverine Marionneau-Lambot, Lucie Brisson, Sandra Geraci, Hathaichanok Impheng, V’yacheslav
Lehen’kyi, Aurelien Haustrate, Adriana Mihalache, Pierre Gosset, Stéphanie Chadet, Stéphanie
Lerondel, Stéphanie Retif, Maryline Le Mée, Julien Sobilo, Sébastien Roger, Gaelle FromontHankard, Mustafa Djamgoz, Philippe Clezardin, Arnaud Monteil, Natalia Prevarskaya. Malignant assignment of neuronal Na+
leak channel, NALCN: governor of Ca2+ oscillations-encoded invadopodogenesis.
bioRxiv 202
0.08.13.249169; doi: https://doi.org/10.1101/2020.08.13.249169


Kasap M, Aamodt EJ, Sagrera CE, Dwyer DS. Novel pharmacological modulation of dystonic
phenotypes caused by a gain-of-function mutation in the Na+ leak-current channel
. Behav Pharmacol.
2020
Aug;31(5):465-476. doi: 10.1097/FBP.0000000000000526.


Kschonsak M, Chua HC, Noland CL, Weidling C, Clairfeuille T, Bahlke OØ, Ameen AO, Li ZR, Arthur
CP, Ciferri C, Pless SA, Payandeh J. Structure of the human sodium leak channel NALCN. Nature.
2020 Jul 22. doi: 10.1038/s41586-020-2570-8.


Lee SY, Vuong TA, Wen X, Jeong HJ, So HK, Kwon I, Kang JS, Cho H. Methylation determines the
extracellular calcium sensitivity of the leak channel NALCN in hippocampal dentate granule cells
.
Exp Mol Med. 2019
Oct 10;51(10):1-14. doi: 10.1038/s12276-019-0325-0.


Ope O, Bhoj EJ, Nelson B, Li D, Hakonarson H, Sobering AK. A homozygous truncating NALCN
variant in two Afro-Caribbean siblings with hypotonia and dolichocephaly
. Am J Med Genet A. 2020
Jul 2. doi: 10.1002/ajmg.a.61744.


Ou M, Zhao W, Liu J, Liang P, Huang H, Yu H, Zhu T, Zhou C. The General Anesthetic Isoflurane
Bilaterally Modulates Neuronal Excitability
. iScience. 2020 Jan 24;23(1):100760. doi:
10.1016/j.isci.2019.100760.


Wie J, Bharthur A, Wolfgang M, Narayanan V, Ramsey K; C4RCD Research Group, Aranda K, Zhang
Q, Zhou Y, Ren D. Intellectual disability-associated UNC80 mutations reveal inter-subunit interaction
and dendritic function of the NALCN channel complex
. Nat Commun. 2020 Jul 3;11(1):3351. doi:
10.1038/s41467-020-17105-8.


Jiongfang Xie, Meng Ke, Lizhen Xu, Shiyi Lin, Jiabei Zhang, Fan Yang, Jianping Wu, Zhen Yan.
Structure of human sodium leak channel NALCN in complex with FAM155A.
bioRxiv
2020.07.24.218958; doi: https://doi.org/10.1101/2020.07.24.218958


Donghang Zhang, Wenling Zhao, Jin Liu, Mengchan Ou, Peng Liang, Jia Li, Yali Chen, Daqing Liao,
Siqi Bai, Jiefei Shen, Xiangdong Chen, Han Huang, Cheng Zhou. Sodium leak channel as a
therapeutic target for neuronal sensitization in neuropathic pain
. bioRxiv 2020.08.17.253534; doi:
https://doi.org/10.1101/2020.08.17.253534

Wie, J., Bharthur, A., Wolfgang, M. et al. Intellectual disability-associated UNC80 mutations reveal inter-subunit interaction and dendritic function of the NALCN channel complex. Nat Commun 11, 3351 (2020). https://doi.org/10.1038/s41467-020-17105-8

Karimi AH, Karimi MR, Farnia P, Parvini F, Foroutan M. A Homozygous Truncating Mutation in NALCN Causing IHPRF1: Detailed Clinical Manifestations and a Review of Literature. Appl Clin Genet. 2020 Aug 27;13:151-157. doi: 10.2147/TACG.S261781. PMID: 32943903; PMCID: PMC7459142.

CLIFAHDD.

Chong JX, McMillin MJ, Shively KM, Beck AE, Marvin CT, Armenteros JR, Buckingham KJ, Nkinsi NT, Boyle EA, Berry MN, Bocian M, Foulds N, Uzielli ML, Haldeman-Englert C, Hennekam RC, Kaplan P, Kline AD, Mercer CL, Nowaczyk MJ, Klein Wassink-Ruiter JS, McPherson EW, Moreno RA, Scheuerle AE, Shashi V, Stevens CA, Carey JC, Monteil A, Lory P, Tabor HK, Smith JD, Shendure J, Nickerson DA; University of Washington Center for Mendelian Genomics, Bamshad MJ. De novo mutations in NALCN cause a syndrome characterized by congenital contractures of the limbs and face, hypotonia, and developmental delay. Am J Hum Genet. 2015 Mar 5;96(3):462-73. doi: 10.1016/j.ajhg.2015.01.003. Epub 2015 Feb 12. PMID: 25683120; PMCID: PMC4375444.