Affinage

NALCN

Sodium leak channel NALCN · UniProt Q8IZF0

Length
1738 aa
Mass
200.3 kDa
Annotated
2026-04-29
80 papers in source corpus 26 papers cited in narrative 26 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NALCN is a voltage-independent, nonselective cation channel that conducts the background sodium leak current essential for setting resting membrane potential and sustaining spontaneous firing in neurons, endocrine cells, and smooth muscle. It assembles with the obligate auxiliary subunits FAM155A (extracellular), UNC79, and UNC80 (intracellular) into a constitutively active channelosome; the UNC79–UNC80 heterodimer tethers to cytoplasmic loops of NALCN, relieves an auto-inhibitory C-terminal interacting helix, and directs dendritic localization, while extracellular divalent cations tonically block the pore (PMID:32494638, PMID:35550517, PMID:33273469). NALCN is bidirectionally controlled by GPCRs: Gq/substance P/M3 muscarinic receptors potentiate the channel through Src family kinases in a G-protein-independent manner mediated by UNC80, whereas Gi/o-coupled receptors (D2, GABAB, α2-adrenergic) inhibit NALCN in a G-protein-dependent manner (PMID:19092807, PMID:19575010, PMID:30556810, PMID:38197879). Gain-of-function mutations in the pore domain cause CLIFAHDD syndrome, loss-of-function mutations cause IHPRF1, and NALCN loss in epithelial tissues promotes cell shedding and metastasis independently of oncogenic transformation (PMID:25683120, PMID:31409833, PMID:36175792).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2007 High

    Identification of the molecular basis of neuronal background Na+ leak: NALCN knockout mice revealed that this single gene encodes the TTX- and Cs+-resistant sodium leak conductance that sets resting membrane potential and is required for respiratory rhythm generation.

    Evidence Nalcn knockout mice with whole-cell patch-clamp in hippocampal neurons and brainstem-spinal cord preparations

    PMID:17448995

    Open questions at the time
    • Mechanism of channel gating unknown
    • Auxiliary subunit composition not yet identified
    • Whether NALCN functions outside the nervous system not addressed
  2. 2008 High

    Discovery that NALCN is under bidirectional GPCR control via distinct signaling modes: substance P/TACR1 activates NALCN through a G-protein-independent, Src kinase-dependent pathway, with UNC80 serving as the scaffold that recruits Src into the channel complex.

    Evidence Whole-cell patch-clamp with pharmacological G-protein and Src kinase blockade, Co-IP in hippocampal and VTA neurons

    PMID:19092807 PMID:19535918

    Open questions at the time
    • Identity of the Src phosphorylation site on NALCN unknown
    • Whether all neuropeptide-activated NALCN currents use the same pathway untested
  3. 2009 High

    Extension of the Src-dependent activation mechanism to a non-neuronal context: M3 muscarinic receptors activate NALCN in pancreatic beta cells, with the NALCN intracellular I–II loop directly interacting with the M3R i3 loop, establishing NALCN as a GPCR effector channel outside the brain.

    Evidence Reciprocal Co-IP, electrophysiology in HEK-293 cells and Xenopus oocytes, domain mapping

    PMID:19575010

    Open questions at the time
    • Physiological role of NALCN in insulin secretion not demonstrated in vivo
    • Stoichiometry of NALCN–GPCR interaction unknown
  4. 2010 High

    Extracellular Ca2+-dependent modulation of NALCN was shown to require a Ca2+-sensing GPCR and G-protein activation, with UNC80 bridging NALCN to UNC79 and the extreme C-terminus of NALCN being essential, revealing a distinct G-protein-dependent inhibitory arm of NALCN regulation.

    Evidence Nalcn and unc79 knockout mice, patch-clamp with GDP-βS, domain deletion analysis

    PMID:21040849

    Open questions at the time
    • Identity of the Ca2+-sensing GPCR not definitively established
    • Whether UNC79 has catalytic or purely scaffolding function unknown
  5. 2015 Medium

    Human genetic disorders were mapped to NALCN: dominant gain-of-function pore mutations cause CLIFAHDD syndrome via a dominant-negative mechanism on wild-type channels, while recessive loss-of-function mutations cause IHPRF1, establishing genotype–phenotype correlations.

    Evidence Exome sequencing with in vitro functional expression studies in multiple families

    PMID:25683120

    Open questions at the time
    • Electrophysiological characterization of individual disease variants limited at this point
    • No animal models recapitulating specific patient mutations
  6. 2016 High

    Cell-type-specific conditional knockouts demonstrated NALCN is required for tonic high-frequency firing in SNr GABAergic neurons and for substance P-activated chemosensory firing in RTN neurons, establishing NALCN as a general determinant of intrinsic neuronal excitability across diverse circuit types.

    Evidence Conditional knockout, scRNA-seq, patch-clamp, in vivo respiratory recording

    PMID:27177420 PMID:27488637

    Open questions at the time
    • Compensatory changes in other leak conductances not fully characterized
    • Downstream behavioral consequences of SNr-specific NALCN loss not reported
  7. 2018 High

    Gi/o-coupled D2 dopamine receptors and GABAB receptors were shown to inhibit NALCN in a G-protein-dependent manner, and NALCN conditional knockout rendered dopaminergic neurons largely silent, defining NALCN as the pacemaker conductance of DA neurons and revealing that inhibitory GPCR regulation uses a mechanistically distinct (G-protein-dependent) pathway from excitatory regulation.

    Evidence Conditional knockout in DA neurons, patch-clamp with GDP-βS and GIRK blockade

    PMID:30556810

    Open questions at the time
    • Which G-protein subunit (Gβγ vs. Gαi) mediates inhibition not resolved
    • Whether D2-NALCN coupling is direct or through intermediary unknown
  8. 2018 High

    NALCN function was extended to smooth muscle: smooth-muscle-specific knockout reduced myometrial excitability and caused dysfunctional labor, demonstrating a non-neuronal physiological role for the Na+ leak channel.

    Evidence Smooth-muscle-specific conditional knockout, current clamp, parturition monitoring

    PMID:30021195

    Open questions at the time
    • Auxiliary subunit expression and complex composition in smooth muscle not determined
    • GPCR modulation of NALCN in myometrium not tested
  9. 2019 High

    Electrophysiological characterization of disease mutations confirmed that IHPRF mutation W1287L is loss-of-function (no current) while CLIFAHDD mutations L509S and Y578S are gain-of-function (increased current density and slowed inactivation), resolving the mechanistic basis of the two opposing channelopathies.

    Evidence Heterologous expression in NG108-15 cells, patch-clamp, site-directed mutagenesis

    PMID:31409833

    Open questions at the time
    • Effects of disease mutations on GPCR modulation not tested
    • Structural basis of gain-of-function gating changes unresolved at this point
  10. 2019 High

    PRMT7-mediated arginine methylation at R1653 was identified as a post-translational mechanism that modulates NALCN by facilitating CaSR/PKC-δ phosphorylation at adjacent S1652, suppressing channel activity and linking methylation status to extracellular Ca2+ sensitivity.

    Evidence In vitro methylation, mutagenesis, electrophysiology in PRMT7 knockout neurons and HEK293T

    PMID:31601786

    Open questions at the time
    • Whether PRMT7 regulation operates in vivo during normal physiology unknown
    • Other arginine methylation sites on NALCN not surveyed
  11. 2020 High

    Reconstitution of the full NALCN channelosome (NALCN + FAM155A + UNC79 + UNC80) in heterologous systems produced constitutively active currents blocked by divalent cations, and cryo-EM at 2.7 Å revealed the NALCN–FAM155A interface, the non-canonical selectivity filter architecture explaining Na+ selectivity and Ca2+ block, and an asymmetric arrangement of two functional voltage sensors.

    Evidence Heterologous co-expression with two-electrode voltage clamp; cryo-EM structure determination

    PMID:32494638 PMID:33273469

    Open questions at the time
    • Structure of full quaternary complex not yet resolved
    • Structural basis of Src-mediated activation unknown
    • Gating transitions not captured
  12. 2020 High

    UNC80's C-terminus was shown to interact with UNC79 and to overcome a soma-retention signal, enabling dendritic localization of the NALCN complex; patient mutations truncating this domain preserve whole-cell currents but abolish dendritic targeting, explaining a clinical phenotype distinct from complete loss-of-function.

    Evidence UNC80 knockout mice, domain deletion, subcellular imaging, Co-IP, patch-clamp

    PMID:32620897

    Open questions at the time
    • Identity of the soma-retention mechanism unknown
    • Whether dendritic vs. somatic NALCN serves distinct signaling functions untested
  13. 2022 High

    Cryo-EM of the full quaternary NALCN–FAM155A–UNC79–UNC80 complex revealed the piler-shaped UNC79–UNC80 heterodimer tethered to NALCN's cytoplasmic loops via three interactions: two required for surface expression and a third that relieves auto-inhibition by displacing the C-terminal interacting helix (CIH), providing a structural mechanism for auxiliary subunit-dependent channel activation.

    Evidence Cryo-EM of quaternary complex with functional validation of localization and auto-inhibition interactions

    PMID:35550517

    Open questions at the time
    • How GPCR signals propagate through the UNC79/UNC80 scaffold to gate the pore structurally unresolved
    • CIH displacement dynamics not captured
  14. 2022 High

    NALCN loss-of-function was discovered to promote epithelial cell shedding from solid tissues into the circulation independently of oncogenic mutations, increasing circulating tumor cells and metastasis; pharmacological blockade with gadolinium phenocopied this effect, revealing a tumor-suppressive role for NALCN channel activity.

    Evidence Conditional knockout in multiple cancer and non-cancer mouse models, Gd3+ treatment, CTC quantification

    PMID:36175792

    Open questions at the time
    • Mechanism by which Na+ leak current prevents cell shedding unknown
    • Whether NALCN status predicts metastasis in human patients not established
  15. 2023 High

    A signaling chain from NALCN Na+ influx → Na+/Ca2+ exchanger activity → intracellular Ca2+ oscillations → Src activation → invadopodia formation was delineated in metastatic prostate cancer cells, providing a mechanistic link between the leak channel and pro-metastatic cytoskeletal remodeling.

    Evidence Live-cell Ca2+ imaging, ion transport inhibitors, Src activity measurement, NALCN knockdown with in vivo invasion assays

    PMID:37278161

    Open questions at the time
    • Whether this Na+→Ca2+ oscillation mechanism operates in neurons or other NALCN-expressing tissues unknown
    • Direct demonstration that Ca2+ oscillations are necessary (not just correlated) for invasion requires further testing
  16. 2023 High

    NALCN was shown to selectively regulate daytime—but not nighttime—repetitive firing in SCN circadian pacemaker neurons, with the effect dependent on rhythmic changes in K+ conductance-driven input resistance, establishing NALCN as a time-of-day-dependent excitability regulator.

    Evidence Conditional knockout, patch-clamp in acute SCN slices, dynamic clamp manipulation

    PMID:37339878

    Open questions at the time
    • Whether circadian regulation involves transcriptional control of NALCN or its auxiliary subunits unknown
    • Behavioral circadian phenotype of SCN-specific NALCN knockout not reported
  17. 2024 High

    α2-Adrenergic receptors were added to the list of Gi/o-coupled inhibitors of NALCN, demonstrated in dorsal cochlear nucleus cartwheel interneurons where NALCN loss abolishes spontaneous firing and α2-adrenergic signal-to-noise modulation of auditory processing.

    Evidence Glycinergic neuron-specific NALCN knockout, patch-clamp, pharmacological receptor activation

    PMID:38197879

    Open questions at the time
    • Whether α2 inhibition uses identical G-protein pathway as D2/GABAB not formally tested
    • Behavioral auditory processing phenotype not assessed
  18. 2025 High

    Neuronal SNARE proteins syntaxin and SNAP25 were identified as inhibitors of NALCN complex activity, and disinhibited NALCN was shown to contribute to neuronal death upon syntaxin depletion, revealing a novel link between vesicle fusion machinery and leak channel regulation.

    Evidence Heterologous expression, primary neuron electrophysiology, syntaxin depletion with NALCN current reduction rescue, cell survival assay

    PMID:40085699

    Open questions at the time
    • Whether SNARE inhibition is direct or via an intermediary unknown
    • Structural basis of SNARE–NALCN interaction not determined
    • In vivo relevance during synaptic transmission not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the structural mechanism by which GPCR signals (both Src-dependent activation and G-protein-dependent inhibition) are transduced through the UNC79/UNC80 scaffold to gate the NALCN pore; the identity and phosphorylation sites through which Src kinases activate the channel; and the molecular basis by which NALCN loss promotes epithelial cell detachment and metastasis.
  • No structure of NALCN in open vs. closed gating states
  • Src phosphorylation site on NALCN/UNC80 not mapped
  • Mechanism linking Na+ leak to cell adhesion not identified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 5 GO:0098772 molecular function regulator activity 1
Localization
GO:0005886 plasma membrane 5
Pathway
R-HSA-112316 Neuronal System 7 R-HSA-382551 Transport of small molecules 3
Partners
FAM155ASLO2.1SNAP25SRCSTX1AUNC79UNC80
Complex memberships
NALCN channelosome (NALCN–FAM155A–UNC79–UNC80)

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 NALCN forms a voltage-independent, nonselective cation channel responsible for the TTX- and Cs+-resistant background Na+ leak conductance in neurons. Knockout mice lack this leak current in hippocampal neurons, have disrupted respiratory rhythm, and die within 24 hours of birth, demonstrating NALCN is required for normal resting membrane potential and neuronal excitability. Knockout mouse model, whole-cell patch-clamp electrophysiology, brain stem-spinal cord recordings Cell High 17448995
2008 Substance P and neurotensin activate a channel complex containing NALCN and a large protein UNC-80 in hippocampal and VTA neurons. Activation by substance P through TACR1 does not require G-protein activation but is dependent on Src family kinases. Whole-cell patch-clamp electrophysiology, pharmacological inhibition of G-proteins and Src kinases, Co-immunoprecipitation Nature High 19092807
2009 UNC80 binds Src kinases and recruits Src into the NALCN channel complex, providing the scaffold for G-protein-independent activation of NALCN by substance P/TACR1. Co-immunoprecipitation, pulldown assays Channels (Austin, Tex.) Medium 19535918
2009 NALCN encodes a current activated by M3 muscarinic receptors in a pancreatic beta-cell line; the current is Src-dependent, G-protein-independent, TTX-resistant, and primarily Na+-permeable. NALCN and M3R belong to the same protein complex, mediated by the intracellular I-II loop of NALCN and the i3 loop of M3R. Whole-cell patch-clamp, Co-immunoprecipitation, heterologous expression in HEK-293 cells and Xenopus oocytes EMBO reports High 19575010
2010 Lowering extracellular Ca2+ activates a NALCN-dependent Na+-leak current (IL-Na) in hippocampal neurons. This coupling requires a Ca2+-sensing GPCR, G-protein activation, UNC80 bridging NALCN to UNC79, and the last amino acid of NALCN's intracellular tail. In nalcn and unc79 knockout mice, IL-Na is insensitive to changes in extracellular Ca2+. Knockout mouse models, whole-cell patch-clamp, pharmacological G-protein manipulation, domain deletion analysis Neuron High 21040849
2015 De novo missense mutations in NALCN affecting residues in or near the S5 and S6 pore-forming segments nearly abolish wild-type NALCN expression and exert a dominant-negative effect, causing CLIFAHDD syndrome, while recessive loss-of-function mutations in other regions cause a distinct autosomal-recessive hypotonia/intellectual disability syndrome. Exome sequencing, in vitro functional expression studies, molecular-inversion probe screening American journal of human genetics Medium 25683120
2016 NALCN is expressed in brainstem retrotrapezoid nucleus (RTN) chemosensory neurons; shRNA-mediated depletion of Nalcn hyperpolarizes RTN neurons, reduces leak Na+ current and firing rate, decreases substance P activation of these neurons, and reduces CO2-evoked neuronal activation and breathing in vivo. shRNA knockdown, whole-cell patch-clamp, in vivo respiratory recording The Journal of neuroscience High 27488637
2016 NALCN is expressed in substantia nigra pars reticulata (SNr) GABAergic neurons and supports their spontaneous high-frequency firing; SNr neurons lacking NALCN have impaired tonic activity. NALCN is also involved in modulation of excitability by glycolysis changes and muscarinic acetylcholine receptors. Single-cell RNA sequencing, conditional knockout, whole-cell patch-clamp eLife High 27177420
2018 D2 dopamine receptors inhibit NALCN-mediated sodium leak currents in dopaminergic neurons via a G-protein-dependent mechanism (blocked by GDP-βS). NALCN conditional knockout dopaminergic neurons are largely silent, demonstrating NALCN is required for pacemaking. GABA-B receptor activation also inhibits NALCN-mediated currents. Conditional knockout, whole-cell patch-clamp, pharmacological G-protein blockade (GDP-βS), GIRK channel blockade eLife High 30556810
2018 NALCN regulates intrinsic excitability of spinal lamina I projection neurons. Substance P activates NALCN current in these neurons through downstream Src kinase signaling; NALCN knockout prevents substance P-evoked action potential discharge. Conditional knockout, whole-cell patch-clamp, pharmacological Src kinase inhibition Pain High 29746349
2019 IHPRF missense mutation p.W1287L abolishes detectable NALCN current (loss-of-function), while CLIFAHDD mutations p.L509S and p.Y578S show higher current densities and slower inactivation (gain-of-function) compared to wild-type NALCN expressed in neuronal NG108-15 cells. Heterologous expression in neuronal cell line, whole-cell patch-clamp electrophysiology, site-directed mutagenesis Scientific reports High 31409833
2019 PRMT7 methylates Arg1653 in the C-terminal region of NALCN; this methylation modulates Ser1652 phosphorylation by CaSR/PKC-delta, which suppresses NALCN activity. PRMT7 deficiency increases NALCN activity and shifts the dose-response curve of NALCN inhibition by extracellular Ca2+, leading to neuronal hyperexcitability. In vitro methylation assay, site-directed mutagenesis, electrophysiology in PRMT7 knockout neurons and HEK293T cells, PKC inhibitor experiments Experimental & molecular medicine High 31601786
2020 Robust NALCN function in heterologous systems requires co-expression of UNC79, UNC80, and FAM155A. The resulting complex is constitutively active, blocked by physiological concentrations of extracellular divalent cations, and modulated by voltage despite fewer voltage-sensing residues than classical Nav/Cav channels. Heterologous expression, two-electrode voltage clamp, pharmacological dissection Science advances High 32494638
2020 UNC80 and UNC79 are subunits of the NALCN complex. UNC80 knockout mice are neonatal lethal. The C-terminus of UNC80 contains a domain that interacts with UNC79 and overcomes a soma-retention signal to achieve dendritic localization of the complex; UNC80 lacking this domain (as in human patients) still supports whole-cell NALCN currents but lacks dendritic localization. Knockout mouse model, Co-immunoprecipitation, domain deletion analysis, subcellular localization imaging, whole-cell patch-clamp Nature communications High 32620897
2020 The cryo-EM structure of rat NALCN and mouse FAM155A complex at 2.7 Å resolution reveals: FAM155A's extracellular cysteine-rich domain interacts directly with NALCN; the non-canonical selectivity filter architecture determines sodium selectivity and calcium block; the asymmetric arrangement of two functional voltage sensors confers voltage modulation. Cryo-EM structure determination at 2.7 Å, structural analysis of selectivity filter and voltage sensors Nature communications High 33273469
2021 TRPC3 and NALCN channels together form sustained inward currents responsible for slow subthreshold depolarization underlying pacemaking in substantia nigra dopaminergic neurons. In TRPC3 knockout mice, NALCN current and expression are upregulated to compensate, maintaining normal pacemaking. TRPC3 knockout mouse model, pharmacological blockade, whole-cell patch-clamp, RT-PCR and protein expression analysis eLife High 34409942
2021 NALCN conducts a Ca2+- and Gd3+-sensitive, TTX-resistant Na+ background conductance in GH3 pituitary endocrine cells. NALCN knockdown hyperpolarizes resting membrane potential and inhibits prolactin secretion; NALCN overexpression depolarizes the RMP. shRNA knockdown, overexpression, whole-cell patch-clamp, prolactin secretion assay FASEB journal High 33793981
2021 Na+ entering myometrial smooth muscle cells through NALCN acts as an intracellular signaling molecule that activates the Na+-activated K+ channel SLO2.1; K+ efflux through SLO2.1 hyperpolarizes the membrane, and decreased SLO2.1/NALCN activity promotes depolarization and uterine contraction. NALCN and SLO2.1 are in close proximity in human MSMCs. Proximity assay (NALCN-SLO2.1 co-localization), electrophysiology, pharmacological dissection iScience Medium 34746693
2022 Cryo-EM structure of the mammalian NALCN-FAM155A-UNC79-UNC80 quaternary complex shows: UNC79-UNC80 form a large piler-shaped heterodimer tethered to the intracellular side of NALCN via tripartite interactions with cytoplasmic loops of NALCN. Two interactions are essential for cell surface localization of NALCN; a third interaction relieves self-inhibition by pulling an auto-inhibitory CTD Interacting Helix (CIH) out of its binding site. Cryo-EM structural determination of quaternary complex, functional validation of localization and self-inhibition interactions Nature communications High 35550517
2022 NALCN loss-of-function promotes epithelial cell shedding from solid tissues into the bloodstream independent of oncogenic mutations, increasing circulating tumor cells and metastases. Gadolinium (a NALCN channel blocker) treatment phenocopied NALCN deletion, increasing CTCs and metastases. Conditional knockout in multiple cancer and non-cancer mouse models, gadolinium pharmacological blockade, CTC quantification Nature genetics High 36175792
2023 NALCN-mediated Na+ influx in metastatic prostate cancer cells maintains intracellular Ca2+ oscillations via a signaling chain involving plasmalemmal and mitochondrial Na+/Ca2+ exchangers, SERCA, and store-operated channels, promoting Src kinase activity, actin remodeling, invadopodia formation, and metastasis. In vitro and in vivo invasion assays, live-cell Ca2+ imaging, ion transport inhibitors, Src kinase activity measurement, NALCN knockdown The EMBO journal High 37278161
2023 NALCN loss in ventral dentate gyrus glutamatergic neurons reduces their excitability and produces depressive-like behaviors. Substance P injection (NALCN activator) into the ventral DG rapidly ameliorated inflammation-induced depression in an NALCN-dependent manner. AAV/lentivirus knockdown, whole-cell patch-clamp, behavioral tests, stereotaxic drug injection Brain, behavior, and immunity High 36796706
2023 NALCN-encoded Na+ leak currents selectively regulate daytime repetitive firing rates of SCN neurons (circadian pacemaker neurons); in vivo conditional knockout reduces daytime firing but not nighttime firing. The effect of NALCN on firing rate depends on K+ current-driven rhythmic changes in input resistance, revealed by dynamic clamp. Conditional knockout, whole-cell patch-clamp in acute SCN slices, dynamic clamp manipulation The Journal of neuroscience High 37339878
2024 NALCN is required for spontaneous firing in cartwheel interneurons of the dorsal cochlear nucleus. Activation of α2-adrenergic receptors and GABAB receptors both inhibit NALCN-mediated currents, suppressing spike generation. α2-dependent enhancement of synaptic strength is also absent in NALCN knockout neurons, linking NALCN to signal-to-noise regulation of auditory processing. Glycinergic neuron-specific NALCN knockout, whole-cell patch-clamp, pharmacological receptor activation eLife High 38197879
2025 Neuronal SNARE proteins syntaxin and SNAP25 inhibit NALCN channel complex activity in both heterologous systems and primary neurons. Reduction of NALCN currents is sufficient to promote cell survival in syntaxin-depleted cells, suggesting disinhibited NALCN contributes to neuronal death in the absence of syntaxin. Heterologous expression, primary neuron electrophysiology, co-expression/depletion experiments, cell survival assay Science advances High 40085699
2018 NALCN contributes a Na+ leak current to myometrial smooth muscle cells. Smooth-muscle-specific NALCN knockout mice have reduced myometrial excitability (shortened action potential bursts) and increased rates of abnormal/dysfunctional labor. Smooth-muscle-specific conditional knockout (MHCCre x NALCNfx/fx), sharp electrode current clamp recordings, parturition outcome monitoring Cellular physiology and biochemistry High 30021195

Source papers

Stage 0 corpus · 80 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 The neuronal channel NALCN contributes resting sodium permeability and is required for normal respiratory rhythm. Cell 280 17448995
2010 Extracellular calcium controls background current and neuronal excitability via an UNC79-UNC80-NALCN cation channel complex. Neuron 162 21040849
2008 Peptide neurotransmitters activate a cation channel complex of NALCN and UNC-80. Nature 130 19092807
2014 The sodium leak channel, NALCN, in health and disease. Frontiers in cellular neuroscience 128 24904279
2015 De novo mutations in NALCN cause a syndrome characterized by congenital contractures of the limbs and face, hypotonia, and developmental delay. American journal of human genetics 120 25683120
2009 The NALCN ion channel is activated by M3 muscarinic receptors in a pancreatic beta-cell line. EMBO reports 92 19575010
2016 Nalcn Is a "Leak" Sodium Channel That Regulates Excitability of Brainstem Chemosensory Neurons and Breathing. The Journal of neuroscience : the official journal of the Society for Neuroscience 73 27488637
2016 The leak channel NALCN controls tonic firing and glycolytic sensitivity of substantia nigra pars reticulata neurons. eLife 62 27177420
2013 Recessive truncating NALCN mutation in infantile neuroaxonal dystrophy with facial dysmorphism. Journal of medical genetics 57 23749988
2020 The NALCN channel complex is voltage sensitive and directly modulated by extracellular calcium. Science advances 55 32494638
2022 The NALCN channel regulates metastasis and nonmalignant cell dissemination. Nature genetics 52 36175792
2018 Gi/o protein-coupled receptors in dopamine neurons inhibit the sodium leak channel NALCN. eLife 51 30556810
2015 A Gain-of-Function Mutation in NALCN in a Child with Intellectual Disability, Ataxia, and Arthrogryposis. Human mutation 46 25864427
2015 Selectivity filters and cysteine-rich extracellular loops in voltage-gated sodium, calcium, and NALCN channels. Frontiers in physiology 42 26042044
2015 UNC80 mutation causes a syndrome of hypotonia, severe intellectual disability, dyskinesia and dysmorphism, similar to that caused by mutations in its interacting cation channel NALCN. Journal of medical genetics 42 26545877
2018 Genetic variants in components of the NALCN-UNC80-UNC79 ion channel complex cause a broad clinical phenotype (NALCN channelopathies). Human genetics 40 30167850
2015 Mutations in UNC80, Encoding Part of the UNC79-UNC80-NALCN Channel Complex, Cause Autosomal-Recessive Severe Infantile Encephalopathy. American journal of human genetics 38 26708753
2016 NALCN channelopathies: Distinguishing gain-of-function and loss-of-function mutations. Neurology 37 27558372
2013 NALCN ion channels have alternative selectivity filters resembling calcium channels or sodium channels. PloS one 37 23383067
2010 Genetic analysis of mouse strains with variable serum sodium concentrations identifies the Nalcn sodium channel as a novel player in osmoregulation. Physiological genomics 34 21177381
2016 De novo missense mutations in NALCN cause developmental and intellectual impairment with hypotonia. Journal of human genetics 31 26763878
2016 A novel homozygous splice site mutation in NALCN identified in siblings with cachexia, strabismus, severe intellectual disability, epilepsy and abnormal respiratory rhythm. European journal of medical genetics 31 26923739
2023 New insights into the physiology and pathophysiology of the atypical sodium leak channel NALCN. Physiological reviews 29 37615954
2019 Functional expression of CLIFAHDD and IHPRF pathogenic variants of the NALCN channel in neuronal cells reveals both gain- and loss-of-function properties. Scientific reports 27 31409833
2018 NALCN channels enhance the intrinsic excitability of spinal projection neurons. Pain 27 29746349
2022 Structure and mechanism of NALCN-FAM155A-UNC79-UNC80 channel complex. Nature communications 26 35550517
2021 TRPC3 and NALCN channels drive pacemaking in substantia nigra dopaminergic neurons. eLife 25 34409942
2019 Methylation determines the extracellular calcium sensitivity of the leak channel NALCN in hippocampal dentate granule cells. Experimental & molecular medicine 25 31601786
2016 Novel NALCN variant: altered respiratory and circadian rhythm, anesthetic sensitivity. Annals of clinical and translational neurology 24 27844033
2011 A co-operative regulation of neuronal excitability by UNC-7 innexin and NCA/NALCN leak channel. Molecular brain 24 21489288
2009 UNC80 functions as a scaffold for Src kinases in NALCN channel function. Channels (Austin, Tex.) 24 19535918
2012 NALCN: a regulator of pacemaker activity. Molecular neurobiology 23 22476981
2020 Intellectual disability-associated UNC80 mutations reveal inter-subunit interaction and dendritic function of the NALCN channel complex. Nature communications 22 32620897
2018 NALCN Dysfunction as a Cause of Disordered Respiratory Rhythm With Central Apnea. Pediatrics 21 29610177
2018 Na+-Leak Channel, Non-Selective (NALCN) Regulates Myometrial Excitability and Facilitates Successful Parturition. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 18 30021195
2017 Biallelic mutations in NALCN: Expanding the genotypic and phenotypic spectra of IHPRF1. American journal of medical genetics. Part A 18 29168298
2023 Loss of sodium leak channel (NALCN) in the ventral dentate gyrus impairs neuronal activity of the glutamatergic neurons for inflammation-induced depression in male mice. Brain, behavior, and immunity 16 36796706
2021 CircRNA NALCN acts as an miR-493-3p sponge to regulate PTEN expression and inhibit glioma progression. Cancer cell international 16 34112159
2020 Structure of voltage-modulated sodium-selective NALCN-FAM155A channel complex. Nature communications 16 33273469
2016 Novel Mutations in the Nonselective Sodium Leak Channel (NALCN) Lead to Distal Arthrogryposis with Increased Muscle Tone. Neuropediatrics 16 27214504
2020 N-benzhydryl quinuclidine compounds are a potent and Src kinase-independent inhibitor of NALCN channels. British journal of pharmacology 15 32436268
2010 The NALCN ion channel is a new actor in pancreatic β-cell physiology. Islets 15 21099296
2023 NALCN-mediated sodium influx confers metastatic prostate cancer cell invasiveness. The EMBO journal 14 37278161
2020 Progesterone and estrogen regulate NALCN expression in human myometrial smooth muscle cells. American journal of physiology. Endocrinology and metabolism 14 31935111
2018 Novel NALCN biallelic truncating mutations in siblings with IHPRF1 syndrome. Clinical genetics 13 29399786
2023 Contributions of the Sodium Leak Channel NALCN to Pacemaking of Medial Ventral Tegmental Area and Substantia Nigra Dopaminergic Neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 12 37640554
2020 A Homozygous Truncating Mutation in NALCN Causing IHPRF1: Detailed Clinical Manifestations and a Review of Literature. The application of clinical genetics 12 32943903
2018 Periodic breathing in patients with NALCN mutations. Journal of human genetics 12 29968795
2017 Post-translational processing and membrane translocation of the yeast regulatory Mid1 subunit of the Cch1/VGCC/NALCN cation channel family. The Journal of biological chemistry 11 29042437
2022 Ultrashort nanosecond electric pulses activate a conductance in bovine adrenal chromaffin cells that involves cation entry through TRPC and NALCN channels. Archives of biochemistry and biophysics 9 35436445
2021 Na+ leak-current channel (NALCN) at the junction of motor and neuropsychiatric symptoms in Parkinson's disease. Journal of neural transmission (Vienna, Austria : 1996) 9 33961117
2021 SLO2.1/NALCN a sodium signaling complex that regulates uterine activity. iScience 9 34746693
2021 The sodium leak channel NALCN regulates cell excitability of pituitary endocrine cells. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 7 33793981
2016 Association Analysis of NALCN Polymorphisms rs1338041 and rs61973742 in a Chinese Population with Isolated Cervical Dystonia. Parkinson's disease 7 27239368
2023 NALCN is a potential biomarker and therapeutic target in human cancers. Frontiers in genetics 6 37152978
2022 Differential modulation of C. elegans motor behavior by NALCN and two-pore domain potassium channels. PLoS genetics 6 35482723
2022 Case Report: A de novo Variant in NALCN Associated With CLIFAHDD Syndrome in a Chinese Infant. Frontiers in pediatrics 6 35911839
2016 Muscle biopsy findings in a child with NALCN gene mutation. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia 6 27473021
2014 Food deprivation and nicotine correct akinesia and freezing in Na(+) -leak current channel (NALCN)-deficient strains of Caenorhabditis elegans. Genes, brain, and behavior 6 24995777
2010 Lack of association of NALCN genetic variants with schizophrenia. Psychiatry research 6 20674038
2024 The Na+ leak channel NALCN controls spontaneous activity and mediates synaptic modulation by α2-adrenergic receptors in auditory neurons. eLife 5 38197879
2023 New presentation of CLIFAHDD syndrome with a novel variant in NALCN gene: A report of a rare case. Clinical case reports 4 37469362
2020 Highly conserved extracellular residues mediate interactions between pore-forming and regulatory subunits of the yeast Ca2+ channel related to the animal VGCC/NALCN family. The Journal of biological chemistry 4 32690610
2018 Lack of current observed in HEK293 cells expressing NALCN channels. Biochimie open 4 29892559
2023 Effects of NALCN-Encoded Na+ Leak Currents on the Repetitive Firing Properties of SCN Neurons Depend on K+-Driven Rhythmic Changes in Input Resistance. The Journal of neuroscience : the official journal of the Society for Neuroscience 3 37339878
2023 Extending and outlining the genotypic and phenotypic spectrum of novel mutations of NALCN gene in IHPRF1 syndrome: identifying recurrent urinary tract infection. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 3 37452996
2022 Severe central sleep apnea in a child with biallelic variants in NALCN. Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine 3 35808948
2024 Case Report: New presentation of CLIFAHDD syndrome with a novel variant in the NALCN gene and a literature review. Frontiers in pediatrics 2 38873579
2024 The background sodium leak channel NALCN is a major controlling factor in pituitary cell excitability. The Journal of physiology 2 39620829
2024 Widening the infantile hypotonia with psychomotor retardation and characteristic Facies-1 Syndrome's clinical and molecular spectrum through NALCN in-silico structural analysis. Frontiers in genetics 2 39722796
2025 The sodium leak channel NALCN is regulated by neuronal SNARE complex proteins. Science advances 1 40085699
2024 NALCN Channels Are Not Major targets of Gα o or Gα q Modulation in the C. elegans Egg-Laying Behavior Circuit. microPublication biology 1 38287929
2024 NALCN Promoter Methylation as a Biomarker for Metastatic Risk in a Cohort of Non-Small Cell Lung Cancer Patients. Biomolecules 1 39766220
2023 Novel NALCN variant linked to temporal lobe epilepsy. American journal of medical genetics. Part A 1 37046053
2023 Malignant currents: sodium leak channel NALCN propels prostate cancer aggressiveness. The EMBO journal 1 37635635
2026 The sodium leak channel NALCN in Drd2+ striatal neurons regulates neuronal excitability, locomotion and food-seeking in a sex-dependent manner. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 0 41673358
2025 Congenital Ataxia with Progressive Cerebellar Atrophy, Camptodactyly, and Hypertrichosis: A Novel Recognizable Phenotype for NALCN Heterozygous Variants. Neuropediatrics 0 39914470
2025 NALCN/Cch1 channelosome subunits originated in early eukaryotes. The Journal of general physiology 0 40910942
2025 A New Variant in the NALCN Channel Is Responsible for Cerebellar Ataxia and Cognitive Impairment. Genes 0 41153398
2023 The Na+ leak channel NALCN controls spontaneous activity and mediates synaptic modulation by α2-adrenergic receptors in auditory neurons. bioRxiv : the preprint server for biology 0 37987013