1. The University of Sydney, Australia
2. University of Copenhagen, Denmark

Abstract

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 (Na_V) and calcium (Ca_V) channels [13, 23]. It possesses distinctive ion selectivity and pharmacological properties compared to these latter ion channels [6, 21]. NALCN, which is insensitive to tetrodotoxin (10 µM), has been proposed to mediate the tetrodotoxin-resistant and voltage-insensitive Na⁺ leak current (I_L-Na) observed in many types of neurone [14]. However, whether NALCN is constitutively active has been challenged [20, 2, 7]. 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 [13, 14]. 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) [6, 3, 12, 24, 10]. 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 [18] and neuronal SNARE complex proteins [21]. 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) [6, 11, 8, 19].

Contents

GtoPdb is an expert-driven guide to pharmacological targets and the substances that act on them. GtoPdb is a reference work which is most usefully represented as an on-line database. As in any publication this work should be appropriately cited, and the papers it cites should also be recognized. This document provides a citation for the relevant parts of the database, and also provides a reference list for the research cited by those parts. For further details see [4].

Please note that the database version for the citations given in GtoPdb are to the most recent preceding version in which the family or its subfamilies and targets were substantially changed. The links below are to the current version. If you need to consult the cited version, rather than the most recent version, please contact the GtoPdb curators.

Database links

References

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