Sodium leak channel non-selective protein (NALCN)

The sodium leak channel non-selective protein (NALCN) is a voltage-independent, non-selective cation channel that serves as the primary mediator of the tetrodotoxin-resistant sodium leak current in neurons [PubMed: 17443180, UniProt]. By facilitating a continuous inward flow of sodium ions, NALCN plays a fundamental role in maintaining the resting membrane potential (RMP) and setting the baseline excitability of the nervous system [Guide to Pharmacology, PubMed: 25161357]. It operates within a large macromolecular complex, or channelosome, involving auxiliary subunits such as UNC79, UNC80, and FAM155A, and its activity is modulated by various G protein-coupled receptors and intracellular signaling pathways [PubMed: 39255294, PubMed: 25161357]. Pathogenic mutations in the NALCN gene lead to severe neurodevelopmental disorders, specifically Infantile Hypotonia with Psychomotor Retardation and Characteristic Facies (IHPRF) and Congenital Contractures of the Limbs and Face, Hypotonia, and Developmental Delay (CLIFAHDD) [PubMed: 23603761, NIH]. Beyond its neurological roles, NALCN has emerged as a potential target in oncology due to its involvement in cancer cell metastasis and as a target for pain management [PubMed: 37089920, PubMed: 38205244]. Currently, no FDA-approved drugs target NALCN selectively, but research continues to explore small-molecule blockers as potential treatments for conditions of neuronal hyper-excitability [Guide to Pharmacology].

Other names

Sodium leak channel non-selectiveVoltage-insensitive sodium channelVoltage-gated channel-like protein 1VGCNL1Can2NALCN-UNC79-UNC80-FAM155A channelosome

Blockade of the non-selective cation pore inhibits the inward sodium leak current, thereby hyperpolarizing the resting membrane potential and reducing cellular excitability [PubMed: 17443180, Guide to Pharmacology].