Affinage

NALCN

Sodium leak channel NALCN · UniProt Q8IZF0

Length
1738 aa
Mass
200.3 kDa
Annotated
2026-06-10
82 papers in source corpus 29 papers cited in narrative 29 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NALCN is the pore-forming subunit of a voltage-independent, nonselective cation channel that generates the TTX- and Cs+-resistant background Na+ leak conductance setting resting membrane potential and supporting tonic/pacemaker firing across diverse excitable cells (PMID:17448995). Functional reconstitution requires an obligate quaternary assembly with the extracellular cysteine-rich FAM155A and the cytoplasmic scaffolds UNC80 and UNC79, which together render the channel constitutively active, permit cell-surface trafficking, and gate its sensitivity to extracellular divalent cations (PMID:32494638, PMID:32620897). Cryo-EM structures show that a non-canonical selectivity filter dictates Na+ selectivity and Ca2+/Mg2+ block, that an asymmetric pair of voltage sensors confers weak voltage modulation, and that the UNC79-UNC80 heterodimer tethers to cytoplasmic loops to relieve auto-inhibition by extracting the channel's own C-terminal interacting helix (PMID:33273469, PMID:35550517). The channel is bidirectionally tuned by neuromodulators: substance P, neurotensin, and muscarinic (M3) agonists potentiate NALCN through G-protein-independent, Src-kinase-dependent signaling scaffolded by UNC80, whereas Gi/o-coupled receptors (D2R, GABA-B, alpha2-adrenergic) and the SNARE proteins syntaxin/SNAP25 inhibit it (PMID:19092807, PMID:19575010, PMID:19535918, PMID:30556810, PMID:38197879, PMID:40085699). Falling extracellular Ca2+ activates NALCN via a Ca2+-sensing GPCR–G-protein–UNC80 pathway acting on the channel's C-terminal tail, and PRMT7-mediated methylation of Arg1653 coupled to CaSR/PKC-delta phosphorylation of Ser1652 suppresses activity (PMID:21040849, PMID:31601786). Physiologically NALCN drives firing of brainstem respiratory/RTN, dopaminergic, SNr GABAergic, SCN circadian, and cochlear cartwheel neurons, sustains pituitary prolactin secretion and myometrial excitability, and its loss-of-function promotes epithelial cell shedding and cancer metastasis (PMID:27488637, PMID:27177420, PMID:30556810, PMID:34409942, PMID:37339878, PMID:38197879, PMID:33793981, PMID:30021195, PMID:36175792). Distinct human disease alleles act through opposing biophysical mechanisms: recessive loss-of-function variants cause IHPRF while de novo pore-domain mutations confer gain- or loss-of-function in CLIFAHDD syndrome (PMID:25683120, PMID:31409833).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2007 High

    Established that NALCN is the molecular basis of the long-postulated neuronal background Na+ leak conductance that sets resting potential, answering what gene underlies tonic depolarizing drive.

    Evidence NALCN-null mice with whole-cell patch-clamp in hippocampal neurons and brainstem recordings

    PMID:17448995

    Open questions at the time
    • Did not define auxiliary subunits or molecular regulation
    • No structural basis for ion selectivity
  2. 2008 High

    Showed NALCN is not a static leak channel but is dynamically activated by neuropeptides via a G-protein-independent, Src-dependent route, revealing a novel non-canonical GPCR signaling mode.

    Evidence Patch-clamp in native neurons plus pharmacology and Co-IP of NALCN/UNC-80

    PMID:19092807

    Open questions at the time
    • Did not identify the scaffold linking GPCRs to Src
    • Direct phosphorylation target on NALCN unmapped
  3. 2009 Medium

    Identified UNC80 as the scaffold recruiting Src into the complex and extended Src-dependent activation to M3 muscarinic receptors, explaining how GPCRs reach NALCN without G-proteins.

    Evidence Co-IP of UNC80-Src; patch-clamp in MIN6/HEK/oocytes and Co-IP mapping M3R i3 loop to NALCN I-II loop

    PMID:19535918 PMID:19575010

    Open questions at the time
    • Single-lab Co-IP for UNC80-Src
    • Stoichiometry and direct phosphosites not defined
  4. 2010 High

    Defined how extracellular Ca2+ controls NALCN, showing a Ca2+-sensing GPCR signals through UNC80/UNC79 to the channel C-terminal tail, connecting ambient divalent levels to leak current.

    Evidence Patch-clamp in NALCN and UNC79 knockout neurons with GPCR/G-protein pharmacology and C-terminal deletion

    PMID:21040849

    Open questions at the time
    • Identity of the Ca2+-sensing receptor in neurons not fully resolved
    • Tail residue mechanism structurally undefined
  5. 2013 Medium

    Demonstrated that alternative splicing of pore selectivity-filter residues (EEEE/EKEE/EEKE) could tune Na+ versus Ca2+ selectivity, addressing the structural determinant of permeation.

    Evidence Molecular cloning and sequence analysis across species; HEK293T transfection

    PMID:23383067

    Open questions at the time
    • No discriminable current above background in heterologous cells
    • Functional selectivity differences not directly measured
  6. 2015 Medium

    Linked NALCN to human disease and showed disease mechanism depends on mutation location, with dominant pore mutations (CLIFAHDD) acting dominant-negatively versus recessive non-pore loss-of-function (IHPRF).

    Evidence Exome sequencing across families plus in vitro expression studies; orthologous mutation in C. elegans nca-1 with behavioral phenotyping

    PMID:25683120 PMID:25864427

    Open questions at the time
    • Dominant-negative inferred from reduced expression, not biophysics
    • Genotype-phenotype mapping incomplete
  7. 2016 High

    Resolved that CLIFAHDD alleles split into gain- and loss-of-function classes and that NALCN sustains tonic firing in specific neuron populations (RTN chemosensory and SNr GABAergic).

    Evidence CRISPR knock-in of patient variants in C. elegans; shRNA/conditional KO with patch-clamp and in vivo plethysmography

    PMID:27177420 PMID:27488637 PMID:27558372

    Open questions at the time
    • C. elegans phenotypes are surrogate for human channel biophysics
    • Circuit-level consequences not fully mapped
  8. 2018 High

    Established bidirectional GPCR control and expanded the physiological roster, showing Gi/o receptors inhibit NALCN G-protein-dependently while NALCN drives dopaminergic pacemaking, nociceptive excitability, and myometrial contractility.

    Evidence Conditional KO with patch-clamp and GDP-beta-S dialysis; spino-PB neuron recordings with Src inhibition; smooth-muscle-specific KO with labor monitoring

    PMID:29746349 PMID:30021195 PMID:30556810

    Open questions at the time
    • Effectors linking G-proteins to channel inhibition undefined
    • Tissue-specific subunit composition unclear
  9. 2019 High

    Provided direct biophysical characterization of WT and disease variants and identified a covalent regulatory layer (PRMT7 arginine methylation coupled to CaSR/PKC-delta phosphorylation) tuning the channel.

    Evidence Patch-clamp of WT/IHPRF/CLIFAHDD variants in NG108-15 cells; in vitro methylation assay, PRMT7-/- electrophysiology, site-directed mutagenesis

    PMID:31409833 PMID:31601786

    Open questions at the time
    • PRMT7 pathway from single lab
    • How methylation/phosphorylation alter gating structurally unknown
  10. 2020 High

    Achieved functional reconstitution and near-atomic structures, defining FAM155A/UNC80/UNC79 as obligate subunits and the selectivity-filter and voltage-sensor architecture, plus UNC80's role in dendritic targeting.

    Evidence Systematic subunit co-expression with two-electrode voltage-clamp; cryo-EM of NALCN-FAM155A at 2.7 A; UNC80 conditional KO with domain dissection and localization; hormone promoter-reporter analysis

    PMID:31935111 PMID:32494638 PMID:32620897 PMID:33273469

    Open questions at the time
    • Full quaternary architecture not yet resolved
    • Hormone regulation shown in single cell type
  11. 2021 Medium

    Extended NALCN's roles to pituitary secretion, SN dopaminergic pacemaking jointly with TRPC3, and downstream Na+-dependent signaling to SLO2.1 and Ca2+ handling, framing NALCN as a signaling hub beyond passive leak.

    Evidence shRNA/overexpression with patch-clamp and secretion assays in GH3 cells; TRPC3 KO with pharmacology and compensatory expression analysis; proximity ligation and pharmacology in myometrial cells

    PMID:33793981 PMID:34409942 PMID:34746693

    Open questions at the time
    • NALCN-SLO2.1 coupling inferred from proximity/pharmacology
    • Compensatory mechanisms not generalized across tissues
  12. 2022 High

    Delivered the complete quaternary cryo-EM mechanism, showing UNC79-UNC80 tether to cytoplasmic loops to both enable surface trafficking and relieve auto-inhibition by displacing the CTD interacting helix; also linked NALCN loss to cell shedding and metastasis.

    Evidence Cryo-EM of NALCN-FAM155A-UNC79-UNC80 with interface mutagenesis and surface-expression assays; conditional Nalcn KO in multiple cancer models with gadolinium treatment

    PMID:35550517 PMID:36175792

    Open questions at the time
    • Conformational changes during gating not captured
    • Mechanism linking channel activity to epithelial shedding unresolved
  13. 2023 Medium

    Detailed a NALCN-initiated Na+/Ca2+ signaling cascade driving cancer invasion and characterized circadian, time-of-day-specific control of SCN firing, deepening physiological and pathological mechanism.

    Evidence Ca2+ imaging, invasion assays, NALCN silencing and in vivo metastasis with NALCN-Src co-localization; conditional KO with patch-clamp and dynamic clamp in SCN

    PMID:37278161 PMID:37339878

    Open questions at the time
    • Invasion cascade contains inferred intermediate steps
    • Directness of NALCN-Src coupling not biochemically resolved
  14. 2024 High

    Showed NALCN underlies cartwheel interneuron spontaneous firing and is the convergent target of alpha2-adrenergic and GABA-B inhibition, refining receptor-channel convergence.

    Evidence Glycinergic-neuron-specific NALCN conditional KO with patch-clamp and receptor pharmacology

    PMID:38197879

    Open questions at the time
    • Shared inhibitory effector for both receptors not identified
  15. 2025 Medium

    Identified SNARE proteins syntaxin/SNAP25 as direct inhibitory partners of NALCN, with functional consequences for cell survival, broadening the channel's regulatory interactome.

    Evidence Co-IP plus electrophysiology in heterologous systems and primary neurons; viability assays in syntaxin-depleted cells

    PMID:40085699

    Open questions at the time
    • Single lab
    • Structural basis of SNARE-NALCN inhibition unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the diverse covalent (methylation/phosphorylation), GPCR, and protein-protein inputs are integrated at the channel during gating, and how loss-of-function mechanistically drives epithelial shedding and metastasis, remain unresolved.
  • No gating-state structure capturing regulatory inputs
  • Tissue-specific subunit/regulator composition incompletely mapped
  • Mechanistic link from channel activity to cell shedding undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 4 GO:0140299 molecular sensor activity 2
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-112316 Neuronal System 4 R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 3
Partners
FAM155APRMT7SLO2.1SNAP25SRCSTX1AUNC79UNC80
Complex memberships
NALCN-FAM155A-UNC80-UNC79 channelosome

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 NALCN forms a voltage-independent, nonselective cation channel that constitutes 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; resting membrane potentials of mutant neurons are insensitive to changes in extracellular Na+ concentration. Genetic knockout (NALCN null mice), whole-cell patch-clamp electrophysiology, brainstem-spinal cord recordings Cell High 17448995
2008 Substance P (via TACR1) and neurotensin activate a cation channel complex containing NALCN and UNC-80 in hippocampal and VTA neurons. The activation by substance P is G-protein-independent but requires Src family kinases. Whole-cell patch-clamp in native neurons and heterologous systems, pharmacological dissection (G-protein inhibitors, Src inhibitors), Co-immunoprecipitation of NALCN/UNC-80 complex Nature High 19092807
2009 UNC80 binds Src kinases and recruits Src into the NALCN channel complex, providing the molecular scaffold for G-protein-independent activation of NALCN by GPCRs. Co-immunoprecipitation (UNC80 pulldown of Src kinases), biochemical complex analysis Channels (Austin, Tex.) Medium 19535918
2009 NALCN is activated by M3 muscarinic receptors in a pancreatic beta-cell line. The current is Na+-selective, TTX-resistant, G-protein-independent, and Src-dependent. NALCN and M3R form a protein complex involving the intracellular I-II loop of NALCN and the i3 loop of M3R. Whole-cell patch-clamp in MIN6 cells and HEK-293 cells, Xenopus oocyte expression, Co-immunoprecipitation EMBO reports High 19575010
2010 Lowering extracellular Ca2+ activates a NALCN-dependent Na+ leak current (I_L-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 C-terminal tail. In nalcn and unc79 knockout neurons, I_L-Na is insensitive to changes in extracellular Ca2+. Whole-cell patch-clamp in cultured hippocampal neurons from knockout mice, pharmacological GPCR/G-protein dissection, molecular deletion of NALCN C-terminal tail Neuron High 21040849
2013 NALCN has alternatively spliced isoforms producing selectivity filter variants: EEEE (calcium channel-like), EKEE, and EEKE (sodium channel-like). Alternative splicing at the high-field-strength site in the pore determines ion selectivity between sodium and calcium. Molecular cloning of alternative splice isoforms, sequence analysis across species, transfection in HEK-293T cells (though no discriminable NALCN current above background was detected in heterologous system) PloS one Medium 23383067
2015 De novo missense mutations in NALCN pore-forming S5/S6 segments (CLIFAHDD syndrome) nearly abolish wild-type NALCN expression in vitro, suggesting a dominant-negative mechanism, distinct from recessive loss-of-function mutations outside the pore that cause IHPRF. In vitro functional expression studies (transfection), exome sequencing, molecular-inversion probe screening American journal of human genetics Medium 25683120
2015 Introducing the human NALCN p.R1181Q gain-of-function mutation into the C. elegans NALCN homologue nca-1 produces a coiling locomotion phenotype identical to established gain-of-function nca alleles, establishing this mutation as conferring gain-of-function properties to the channel. Genetic introduction of orthologous mutation in C. elegans, behavioral phenotype analysis Human mutation Medium 25864427
2016 CLIFAHDD-causing mutations in NALCN divide into gain-of-function and loss-of-function categories when engineered into C. elegans nca ortholog by CRISPR-Cas9: half phenocopy gain-of-function (hypercontraction) and half phenocopy loss-of-function mutants. CRISPR-Cas9 engineering of human mutations into C. elegans NCA, behavioral phenotyping Neurology Medium 27558372
2016 NALCN is expressed in CO2/H+-sensitive RTN neurons and provides the leak Na+ current that supports their tonic firing. shRNA depletion of Nalcn hyperpolarizes RTN neurons, reduces leak Na+ current and firing rate, and decreases substance P-evoked activation (but not serotonin or pH-sensitive K+ currents). In vivo RTN-specific Nalcn knockdown reduces CO2-evoked neuronal activation and breathing. shRNA knockdown in vivo and ex vivo, whole-cell patch-clamp, in vivo plethysmography, immunohistochemistry The Journal of neuroscience High 27488637
2016 NALCN is expressed in SNr GABAergic neurons and is required for their spontaneous tonic firing. SNr neurons lacking NALCN have impaired spontaneous activity. NALCN also mediates excitability modulation by glycolytic changes and by muscarinic acetylcholine receptor activation in SNr neurons. Single-cell RNA sequencing to identify NALCN expression, conditional NALCN knockout, whole-cell patch-clamp eLife High 27177420
2018 D2 dopamine receptor activation inhibits NALCN-mediated sodium leak currents in dopaminergic neurons through a G-protein-dependent mechanism (blocked by intracellular GDP-βS). GABA-B receptor activation also inhibits NALCN currents. NALCN is required for spontaneous pacemaking in dopaminergic neurons; conditional NALCN knockout neurons are predominantly silent. Whole-cell patch-clamp in wild-type vs. NALCN conditional knockout dopaminergic neurons, pharmacological GPCR activation, GDP-βS intracellular dialysis eLife High 30556810
2018 NALCN contributes to myometrial excitability and parturition. Smooth-muscle-specific NALCN knockout mice have reduced myometrial excitability (shortened action potential bursts) and increased rate of abnormal/dysfunctional labor. Smooth-muscle-specific conditional knockout (NALCNfx/fx × MHCCre mice), sharp electrode current clamp recordings, labor outcome monitoring Cellular physiology and biochemistry High 30021195
2019 IHPRF missense mutation p.W1287L results in loss of NALCN current (loss-of-function), while CLIFAHDD mutations p.L509S and p.Y578S produce higher NALCN current densities and slower inactivation (gain-of-function). Wild-type NALCN current shows Na+-dependence, Gd3+ block, TTX resistance, potentiation by low extracellular Ca2+, and voltage-sensitive inactivation. Heterologous expression in neuronal NG108-15 cell line, whole-cell patch-clamp electrophysiology with disease variant comparison Scientific reports High 31409833
2019 PRMT7-mediated arginine methylation at Arg1653 of NALCN suppresses channel activity. Loss of PRMT7 increases NALCN activity by shifting extracellular Ca2+ dose-response toward inhibition, and methylation of Arg1653 modulates adjacent Ser1652 phosphorylation by CaSR/PKC-delta, thereby linking extracellular Ca2+ sensing to NALCN suppression. In vitro methylation assay (PRMT7 methylates NALCN Arg1653), electrophysiology in PRMT7-/- neurons, site-directed mutagenesis of Arg1653/Ser1652, PKC inhibitor treatment, HEK293T overexpression Experimental & molecular medicine Medium 31601786
2020 Robust functional NALCN expression in heterologous systems requires co-expression of UNC79, UNC80, and FAM155A. The resulting NALCN channel complex is constitutively active, conducts monovalent cations, is blocked by physiological concentrations of extracellular divalent cations (Ca2+/Mg2+), and is modulated by voltage despite fewer voltage-sensing residues than canonical voltage-gated channels. Heterologous expression in Xenopus oocytes with systematic subunit co-expression, two-electrode voltage-clamp, pharmacology Science advances High 32494638
2020 Cryo-EM structure of rat NALCN and mouse FAM155A complex resolved at 2.7 Å. The non-canonical selectivity filter architecture dictates sodium selectivity and calcium block. Asymmetric arrangement of two functional voltage sensors explains voltage modulation. FAM155A interacts with NALCN through an extracellular cysteine-rich domain. Cryo-EM structure determination at 2.7 Å resolution Nature communications High 33273469
2020 UNC80 and UNC79 are bona fide 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 NALCN complex. UNC80 truncations lacking this C-terminal domain (as found in human patients) maintain whole-cell NALCN currents but abolish dendritic localization. UNC80 conditional knockout mice (neonatal lethality), whole-cell patch-clamp, domain deletion analysis, subcellular localization (dendritic vs. somatic), Co-immunoprecipitation Nature communications High 32620897
2021 TRPC3 and NALCN channels together generate the sustained inward current responsible for subthreshold slow depolarization and pacemaking in substantia nigra dopaminergic neurons. NALCN compensates for loss of TRPC3 (NALCN mRNA, protein, and current are upregulated in TRPC3 KO mice); blocking NALCN abolishes pacemaking in both WT and TRPC3 KO mice. TRPC3 KO mice, pharmacological blockade of TRPC3 and NALCN separately, whole-cell patch-clamp, qPCR/western blot for compensatory upregulation eLife High 34409942
2021 NALCN conducts a Ca2+/Gd3+-sensitive, TTX-resistant Na+ background current in pituitary GH3 cells. NALCN knockdown hyperpolarizes the resting membrane potential, alters electrical properties, and inhibits prolactin secretion; NALCN overexpression has opposite effects. shRNA knockdown, NALCN overexpression, whole-cell patch-clamp, secretion assay in GH3 cells FASEB journal Medium 33793981
2021 Na+ entering through NALCN acts as an intracellular signaling molecule that activates the Na+-activated K+ channel SLO2.1. NALCN and SLO2.1 are in close proximity in myometrial smooth muscle cells and functionally couple to regulate membrane potential: decreased SLO2.1/NALCN activity induces membrane depolarization and Ca2+ entry to promote contraction. Proximity ligation assay (NALCN and SLO2.1 co-localization), pharmacological dissection, patch-clamp in MSMCs iScience Medium 34746693
2022 Cryo-EM structure of the mammalian NALCN-FAM155A-UNC79-UNC80 quaternary complex. UNC79-UNC80 form a pillar-shaped heterodimer tethered to the intracellular face of NALCN through tripartite interactions with cytoplasmic loops. Two of three interactions are essential for cell surface localization of NALCN; one interaction relieves NALCN self-inhibition by pulling the auto-inhibitory CTD Interacting Helix (CIH) out of its binding site. Cryo-EM structure of quaternary complex, mutagenesis of interaction interfaces, cell surface expression assays Nature communications High 35550517
2022 NALCN loss-of-function increases circulating tumor cells and metastasis in gastric, intestinal, and pancreatic adenocarcinoma mouse models, and also causes shedding of normal epithelial cells into blood in non-tumor-bearing mice, demonstrating NALCN regulates cell shedding from solid tissues independent of malignancy. Tissue-specific conditional Nalcn knockout in multiple mouse cancer models, gadolinium (NALCN channel blocker) pharmacological treatment, CTC enumeration, histological analysis of distant organs Nature genetics High 36175792
2023 NALCN-mediated Na+ influx in metastatic prostate cancer cells initiates Ca2+ oscillations via a signaling chain including plasmalemmal and mitochondrial Na+/Ca2+ exchangers, SERCA, and store-operated channels. This cascade promotes Src kinase activity (co-localized with NALCN), actin remodeling, secretion of proteolytic enzymes, and invasive potential in vitro and in vivo. In vitro invasion assays, Ca2+ imaging, ion channel pharmacology, NALCN silencing, in vivo metastasis model, proximity co-localization of NALCN and Src The EMBO journal Medium 37278161
2023 NALCN-encoded Na+ leak currents are similar in amplitude during day and night in SCN neurons, but differentially modulate daytime (not nighttime) repetitive firing rates. In vivo conditional NALCN knockout selectively reduces daytime firing rates. The effect of NALCN on SCN firing depends on K+ current-driven rhythmic changes in input resistance (dynamic clamp manipulation). In vivo conditional knockout, whole-cell patch-clamp in acute SCN slices, dynamic clamp manipulation of Na+ and K+ currents The Journal of neuroscience High 37339878
2024 In dorsal cochlear nucleus cartwheel interneurons, NALCN is required for spontaneous firing. Activation of α2-adrenergic receptors inhibits NALCN and suppresses spontaneous firing (effect absent in glycinergic neuron-specific NALCN knockout). GABA-B receptors also inhibit NALCN, acting on the same population of channels as α2 receptors. α2-dependent enhancement of synaptic strength also requires NALCN. Glycinergic neuron-specific NALCN conditional knockout, whole-cell patch-clamp, pharmacological receptor activation/blockade eLife High 38197879
2025 Neuronal SNARE proteins syntaxin and SNAP25 physically interact with and inhibit NALCN channel complex activity. This interaction was demonstrated in both heterologous systems and primary neurons, and reduction of NALCN currents is sufficient to promote cell survival in syntaxin-depleted cells. Co-immunoprecipitation (syntaxin/SNAP25 interaction with NALCN complex), electrophysiology in heterologous systems and primary neurons, cell viability assays in syntaxin-depleted cells Science advances Medium 40085699
2020 Hormone regulation of NALCN in myometrial smooth muscle: progesterone increases NALCN mRNA (5.6-fold) and protein expression and enhances NALCN-dependent leak current, while estrogen decreases NALCN expression (2.3-fold) and inhibits the leak current. Progesterone response elements (PREs) in the NALCN promoter mediate this regulation (confirmed by luciferase assays), but the estrogen response element (ERE) does not contribute. qRT-PCR, western blot, patch-clamp electrophysiology, promoter luciferase reporter assay in human MSMCs American journal of physiology. Endocrinology and metabolism Medium 31935111
2018 Substance P activates NALCN current in spino-parabrachial projection neurons through downstream Src kinase signaling. Genetic deletion of NALCN prevents substance P-evoked action potential discharge in these nociceptive projection neurons and reduces intrinsic excitability. NALCN conditional knockout, whole-cell patch-clamp in lamina I spino-PB neurons, pharmacological Src kinase inhibition Pain Medium 29746349

Source papers

Stage 0 corpus · 82 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 282 17448995
2010 Extracellular calcium controls background current and neuronal excitability via an UNC79-UNC80-NALCN cation channel complex. Neuron 163 21040849
2014 The sodium leak channel, NALCN, in health and disease. Frontiers in cellular neuroscience 131 24904279
2008 Peptide neurotransmitters activate a cation channel complex of NALCN and UNC-80. Nature 130 19092807
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 122 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 53 36175792
2018 Gi/o protein-coupled receptors in dopamine neurons inhibit the sodium leak channel NALCN. eLife 52 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 41 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
2013 NALCN ion channels have alternative selectivity filters resembling calcium channels or sodium channels. PloS one 38 23383067
2016 NALCN channelopathies: Distinguishing gain-of-function and loss-of-function mutations. Neurology 37 27558372
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
2023 New insights into the physiology and pathophysiology of the atypical sodium leak channel NALCN. Physiological reviews 33 37615954
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
2018 NALCN channels enhance the intrinsic excitability of spinal projection neurons. Pain 28 29746349
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
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 25 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 17 36796706
2020 Structure of voltage-modulated sodium-selective NALCN-FAM155A channel complex. Nature communications 17 33273469
2021 CircRNA NALCN acts as an miR-493-3p sponge to regulate PTEN expression and inhibit glioma progression. Cancer cell international 16 34112159
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
2022 Differential modulation of C. elegans motor behavior by NALCN and two-pore domain potassium channels. PLoS genetics 7 35482723
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
2024 The Na+ leak channel NALCN controls spontaneous activity and mediates synaptic modulation by α2-adrenergic receptors in auditory neurons. eLife 6 38197879
2023 NALCN is a potential biomarker and therapeutic target in human cancers. Frontiers in genetics 6 37152978
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
2023 New presentation of CLIFAHDD syndrome with a novel variant in NALCN gene: A report of a rare case. Clinical case reports 4 37469362
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 4 35808948
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
2024 NALCN Channels Are Not Major targets of Gα o or Gα q Modulation in the C. elegans Egg-Laying Behavior Circuit. microPublication biology 2 38287929
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
2024 NALCN Promoter Methylation as a Biomarker for Metastatic Risk in a Cohort of Non-Small Cell Lung Cancer Patients. Biomolecules 2 39766220
2025 The sodium leak channel NALCN is regulated by neuronal SNARE complex proteins. Science advances 1 40085699
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
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 1 37987013
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
2026 An improved electrophysiological cellular assay to unlock the pharmacological modulation of the NALCN channelosome. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 0 42068819
2026 Reversible high-fat ketogenic formula-induced hypertriglyceridemia in a child with NALCN mutation on a ketogenic diet: a case report. Molecular biology reports 0 42159795
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

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