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Sodium leak channel, non-selective (NALCN) C
Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
Overview
The sodium leak channel, non selective (NALCN) is a member of the family of four-domain voltage-gated cation channels that include voltage-gated sodium (NaV) and calcium (CaV) channels [12,22]. It possesses distinctive ion selectivity and pharmacological properties compared to these latter ion channels [5,20]. NALCN, which is insensitive to tetrodotoxin (10 µM), has been proposed to mediate the tetrodotoxin-resistant and voltage-insensitive Na+ leak current (IL-Na) observed in many types of neurone [13]. However, whether NALCN is constitutively active has been challenged [2,6,19]. NALCN is widely distributed within the central nervous system and is also expressed in the heart and pancreas specifically, in rodents, within the islets of Langerhans [12-13]. There is now strong functional and structural evidence indicating that NALCN forms a channelosome with obligatory auxiliary subunits UNC79, UNC80 and FAM155A (also known as NALF1) [3,5,9,11,23]. NALCN is the pore-forming α subunit, UNC79 and UNC80 are massive HEAT-repeat proteins that form an intertwined anti-parallel superhelical assembly that docks intracellularly onto NALCN. FAM155A forms an extracellular dome that shields extracellular access pathways to the selective filter of NALCN. There is also increasing evidence suggesting that the NALCN-UNC79-UNC80-FAM155A channelosome is modulated by additional auxiliary subunits including G proteins [17] and neuronal SNARE complex proteins [20]. However, there remain many areas of uncertainty surrounding NALCN function.
It is worth noting that there is currently no NALCN-specific pharmacology. Inhibitors include multivalent cations (Gd3+, Ca2+, Mg2+, Ba2+, Zn2+) and small molecules (verapamil, 2-APB, DPBA, fluvastatin, L-703,606) [5,7,10,18].
Channels and Subunits
Targets of relevance to immunopharmacology are highlighted in blue
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NALCN C Show summary » |
Comments
Further reading
Citation information
Database page citation:
Han Chow Chua, Stephan A. Pless. Sodium leak channel, non-selective (NALCN). Accessed on 12/09/2025. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=126.
Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Mathie AA, Peters JA, Veale EL, Striessnig J, Kelly E, Armstrong JF, Faccenda E, Harding SD, Davies JA et al. (2023) The Concise Guide to PHARMACOLOGY 2023/24: Ion channels. Br J Pharmacol. 180 Suppl 2:S145-S222.
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It has been previously suggested that NALCN function is modulated by different signaling molecules/proteins including NK1, neurotensin, M3R, G proteins, Src tyrosine kinases and CaSR [14,14,14-15,19,19,21]. There is an expansive body of evidence indicating that NALCN forms a complex with UNC79, UNC80 and FAM155 [16]. Clinical reports indicate that NALCN variants cause severe neurodevelopmental disorders including CLIFAHDD (congenital contractures of the limbs and face, hypotonia, and developmental delay), and IHPRF1 (infantile hypotonia with psychomotor retardation and characteristic facies-1) and -2 [1,4,8].