Affinage

NCS1

Neuronal calcium sensor 1 · UniProt P62166

Length
190 aa
Mass
21.9 kDa
Annotated
2026-06-10
74 papers in source corpus 33 papers cited in narrative 33 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NCS-1 is a myristoylated EF-hand calcium sensor that transduces intracellular Ca2+ signals into the regulation of membrane trafficking, receptor signaling, and synaptic plasticity through direct protein-protein interactions (PMID:7806504, PMID:8799187). Biophysically it carries two active divalent-cation EF-hands that bind Ca2+ with strong positive cooperativity and a Mg2+-saturated state resembling the Ca2+-bound conformation (PMID:7806504), and its N-terminal pseudoEF-hand stabilizes the functional EF-hands, with mu-calpain cleavage of this region sharply lowering Ca2+ affinity (PMID:19732951). As an effector, NCS-1 binds and stimulates the lipid kinase PI4Kbeta in a myristoylation-dependent manner at the Golgi to drive vesicular trafficking and regulated exocytosis, an axis it shares with ARF GTPases (PMID:11526106, PMID:17555535). In neurons NCS-1 controls dopaminergic signaling: it associates with the D2 dopamine receptor and GRK2 to limit agonist-induced D2R phosphorylation and internalization, enhancing D2R-mediated cAMP inhibition, and promotes Ca2+-dependent D2R exocytosis to the surface (PMID:12351722, PMID:41211723). This NCS-1/D2R interface underlies non-desensitizing D2-autoreceptor responses and supports hippocampal LTP, exploratory behavior, and spatial memory (PMID:24934288, PMID:19755107). NCS-1 is also a Ca2+-dependent regulator of intracellular Ca2+ release: it binds the IP3R suppressor domain through Leu-89 in its hydrophobic pocket to increase channel open probability and InsP3-dependent Ca2+ release, and forms a trimeric complex with WFS1 and the IP3R at ER-mitochondria contacts to promote ER-to-mitochondria Ca2+ transfer, with NCS-1 re-expression rescuing mitochondrial dysfunction in Wolfram syndrome models (PMID:31659121, PMID:20801127, PMID:30352948, PMID:36320410). At the synapse it negatively regulates the G-protein chaperone/GEF Ric-8A by inducing a conformational rearrangement that excludes Galpha and blocks casein kinase II phosphorylation in a Ca2+-reversible manner, controlling synapse number through a Frq/NCS-1–Ric8a–Galphas pathway (PMID:38018500, PMID:25074811). Small molecules targeting the NCS-1 hydrophobic crevice (FD44 and FDA-approved compounds) disrupt the NCS-1/Ric8a or NCS-1/D2R interfaces and rescue synaptic and learning phenotypes, including in a Drosophila fragile X model (PMID:28119500, PMID:41211723).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1994 High

    Establishing the cation-binding logic of NCS-1 was required to understand how it senses Ca2+; the protein was shown to operate through two cooperative EF-hands with a Mg2+-primed conformation.

    Evidence Flow dialysis, fluorescence, CD and thiol-reactivity on purified recombinant protein

    PMID:7806504

    Open questions at the time
    • Does not connect cation occupancy to specific effector engagement
    • No structural model of the Ca2+-bound state
  2. 1996 High

    To test whether NCS-1 acts as a calmodulin-like sensor, it was shown to activate Ca2+/calmodulin-dependent enzymes and substitute for calmodulin in vivo, defining it as a multivalent Ca2+ effector.

    Evidence In vitro enzyme assays (PDE, calcineurin, NOS) and Paramecium cam1 complementation

    PMID:8799187

    Open questions at the time
    • Physiological relevance of these enzyme targets in mammalian neurons unclear
    • Does not establish endogenous partners
  3. 2001 High

    The first defined mammalian effector pathway was established: NCS-1 binds and stimulates PI4Kbeta in a myristoylation-dependent manner at the Golgi, linking the sensor to vesicular trafficking.

    Evidence Co-IP, in vitro kinase assay, myristoylation-defective mutant, Golgi co-localization in COS-7 cells

    PMID:11526106

    Open questions at the time
    • Cargo specificity of NCS-1/PI4Kbeta trafficking not defined
    • Role of Ca2+ vs myristoylation in activation not fully separated
  4. 2002 High

    NCS-1 was placed in dopaminergic signaling by showing it limits D2R desensitization through reduced GRK2-mediated phosphorylation, requiring intact Ca2+ binding.

    Evidence Reciprocal Co-IP from striatal neurons, cAMP and internalization assays, Ca2+-binding mutant

    PMID:12351722

    Open questions at the time
    • Structural basis of the NCS-1/D2R interface not resolved here
    • Whether NCS-1 acts directly on GRK2 or via D2R unresolved
  5. 2008 High

    NCS-1 was identified as the Ca2+ sensor selectively required for mGluR-LTD via Ca2+-dependent binding to PICK1, distinguishing it from NMDAR-dependent plasticity.

    Evidence Perirhinal slice electrophysiology, direct binding assay, dominant-negative PICK1 BAR fusion

    PMID:19109914

    Open questions at the time
    • Downstream effectors of NCS-1/PICK1 in LTD not defined
    • PICK1 BAR-domain binding interface on NCS-1 not mapped
  6. 2009 High

    Genetic gain-of-function with pharmacological rescue placed NCS-1 upstream of D2R in hippocampal plasticity and memory, linking the molecular interaction to behavior.

    Evidence Inducible DG overexpression, LTP recording, behavior, DNIP peptide and D2R antagonist rescue

    PMID:19755107

    Open questions at the time
    • Endogenous (non-overexpression) requirement not addressed here
    • Circuit-level mechanism downstream of D2R unresolved
  7. 2009 High

    A Drosophila null established a PI4Kbeta-independent function of NCS-1, modulating voltage-gated Ca2+ entry via cacophony to control neurotransmitter release and terminal growth.

    Evidence frq-null genetics, frq/cacophony epistasis, electrophysiology, PI4Kbeta-null background

    PMID:19861494

    Open questions at the time
    • Direct physical interaction with the channel not shown
    • Mammalian counterpart of this channel modulation not established
  8. 2010 High

    NCS-1 was shown to act as a positive regulator of IP3R channel gating, increasing open probability and InsP3-dependent Ca2+ release, with relevance to paclitaxel-induced Ca2+ dysregulation.

    Evidence Single-channel patch-clamp, shRNA knockdown, Ca2+ imaging in cardiomyocytes

    PMID:20801127

    Open questions at the time
    • Binding site on IP3R not mapped in this study
    • Ca2+ dependence of the modulation not fully defined
  9. 2014 High

    Crystallography and genetics defined NCS-1 as a negative regulator of Ric8a within a Frq/NCS-1–Ric8a–Galphas pathway controlling synapse number, with binding specificity traced to residues R94/T138.

    Evidence Frq2 crystal structure, Frq1 mutagenesis, genetic epistasis, Co-IP, synapse counting (Drosophila)

    PMID:25074811

    Open questions at the time
    • Mechanism by which NCS-1 inhibits Ric8a not yet structural at the complex level
    • Conservation of synapse phenotype in mammals not shown
  10. 2014 High

    The non-desensitizing D2-autoreceptor phenotype in adult dopamine neurons was shown to require a Cav1.3-Ca2+-driven NCS-1/D2R interaction, ordering the mechanistic chain.

    Evidence SN slice electrophysiology, Cav1.3 pharmacology/genetics, in vivo cocaine/L-DOPA paradigm

    PMID:24934288

    Open questions at the time
    • Molecular trigger linking Cav1.3 Ca2+ to NCS-1/D2R binding unresolved
    • Direct measurement of the interaction in vivo not provided
  11. 2017 High

    A crystal structure of NCS-1 with the inhibitor FD44 confirmed the regulatory mechanism: ligand stabilization of the mobile C-terminal helix sterically blocks Ric8a binding and rescues a fragile X model.

    Evidence X-ray crystallography of NCS-1/FD44, SAR with analogs, Drosophila FXS behavioral/synapse rescue

    PMID:28119500

    Open questions at the time
    • Therapeutic translation to mammalian FXS not shown
    • Selectivity over other NCS family proteins not established
  12. 2018 High

    NCS-1 was placed at ER-mitochondria contact sites in a WFS1–NCS-1–IP3R complex that promotes ER-to-mitochondria Ca2+ transfer, linking it to Wolfram syndrome pathophysiology.

    Evidence Reciprocal Co-IP, live-cell Ca2+ imaging, mitochondrial assays, rescue in WFS1-null patient fibroblasts

    PMID:30352948

    Open questions at the time
    • How WFS1 controls NCS-1 abundance not mechanistically defined
    • Stoichiometry/architecture of the trimeric complex unknown
  13. 2019 High

    The IP3R interaction was mapped to the receptor suppressor domain (residues 66-110) and to Leu-89 in the NCS-1 hydrophobic pocket, linking the interaction to Ca2+ signaling and cancer cell survival.

    Evidence Docking, Co-IP, blocking peptides, Leu-89 mutagenesis, Ca2+ imaging and survival assays in breast cancer cells

    PMID:31659121

    Open questions at the time
    • Whether the same pocket mediates other partner interactions not tested here
    • In vivo relevance of Leu-89 variants not established
  14. 2023 High

    High-resolution structure and reconstitution defined a Ca2+-reversible switch: NCS-1 traps Ric-8A in a Galpha- and CK2-inaccessible conformation, with mutual exclusivity of NCS-1 and Galpha binding.

    Evidence In vitro reconstitution, GEF activity assay, phosphorylation assay, X-ray crystallography of NCS-1/Ric-8A

    PMID:38018500

    Open questions at the time
    • Cellular Ca2+ thresholds governing the switch not measured
    • Physiological consequences in mammalian synapses not shown
  15. 2025 Medium

    NCS-1 was shown to drive Ca2+-dependent exocytic delivery of D2R to the plasma membrane, and FDA-approved drugs targeting its hydrophobic crevice were shown to disrupt the NCS-1/D2R interaction.

    Evidence In vitro binding, cell-based D2R surface assay, structural studies, FDA-drug screen

    PMID:41211723

    Open questions at the time
    • In vivo efficacy of the drugs not established
    • Relationship between trafficking role and the earlier desensitization role not unified

Open questions

Synthesis pass · forward-looking unresolved questions
  • How NCS-1 selects among its many competing partners (PI4Kbeta, D2R, IP3R, Ric-8A, channels) under defined Ca2+ and subcellular conditions, and how this is coordinated in vivo, remains unresolved.
  • No quantitative model of partner selection vs Ca2+ occupancy
  • Many interactions rest on single-lab or correlational data (e.g. IR, Kv4.2)
  • Endogenous, tissue-specific functions of mammalian NCS-1 incompletely mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0140299 molecular sensor activity 3
Localization
GO:0005783 endoplasmic reticulum 2 GO:0005794 Golgi apparatus 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 3 R-HSA-5653656 Vesicle-mediated transport 3
Partners
ARF1DRD2GRK2ITPR1PI4KBPICK1RIC8AWFS1
Complex memberships
WFS1–NCS-1–IP3R ER-mitochondria complex

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 NCS-1 attenuates agonist-induced D2 dopamine receptor internalization by reducing D2 receptor phosphorylation, thereby enhancing D2 receptor-mediated cAMP inhibition after dopamine stimulation. This effect requires intact calcium-binding properties of NCS-1 (abolished by single amino acid mutation). NCS-1 co-immunoprecipitates with both the D2 receptor and GRK2 in striatal neurons. Co-immunoprecipitation from striatal neurons, HEK293 cell expression system, cAMP assay, receptor internalization assay, calcium-binding mutant The Journal of neuroscience High 12351722
2001 NCS-1 physically associates with phosphatidylinositol 4-kinase beta (PI4Kbeta) and stimulates its lipid kinase activity; this stimulation requires N-terminal myristoylation of NCS-1. In COS-7 cells, NCS-1 and PI4Kbeta form a co-immunoprecipitable complex and co-localize at the Golgi; PI4K activity is present in anti-NCS-1 immunoprecipitates. Co-expression affects vesicular trafficking (large perinuclear vesicle phenotype blocked by catalytically inactive PI4Kbeta) and increases Ca2+-stimulated phosphatidylinositol 4-phosphate synthesis. Co-immunoprecipitation, in vitro kinase assay, myristoylation-defective mutant, YFP co-localization in COS-7 cells, radiolabeled lipid kinase assay in permeabilized cells The Journal of biological chemistry High 11526106
1996 NCS-1 directly activates two Ca2+/calmodulin-dependent enzymes — 3':5'-cyclic nucleotide phosphodiesterase and protein phosphatase calcineurin — in vitro, and co-activates nitric oxide synthase synergistically with calmodulin. NCS-1 can substitute for calmodulin in vivo in calmodulin-defective cam1 Paramecium to partially restore wild-type behavioral responses. In vitro enzyme activity assays (PDE, calcineurin, NOS), in vivo complementation in calmodulin-defective Paramecium Proceedings of the National Academy of Sciences of the United States of America High 8799187
1994 NCS-1 possesses exactly two active divalent cation-binding sites (EF-hands), binds Ca2+ with very strong positive cooperativity (Hill coefficient ~2.0) with allosteric affinity enhancement of ~1600-fold between the two sites, and binds Mg2+ with high affinity (K'Mg ~8.3×10^4 M-1) such that the Mg2+-saturated form adopts a conformation resembling the Ca2+-bound form. A unique Cys-38 in EF-hand site I shows differential reactivity depending on metal occupancy. Flow dialysis, equilibrium gel filtration, Trp fluorescence spectroscopy, near-UV CD, DTNB thiol reactivity assays The Journal of biological chemistry High 7806504
2008 NCS-1 is the Ca2+ sensor required for mGluR-LTD (but not NMDAR-LTD) in perirhinal cortex synapses. NCS-1 binds directly to PICK1 via PICK1's BAR domain in a Ca2+-dependent manner; this NCS-1–PICK1 association is stimulated by mGluR activation. Blocking this interaction with a PICK1 BAR domain fusion protein specifically abolishes mGluR-LTD. Electrophysiology (LTD recording in perirhinal cortex slices), direct binding assay, dominant-negative peptide/fusion protein interference, pharmacological dissection (IP3, PKC inhibitors) Neuron High 19109914
2009 Modest NCS-1 overexpression in adult murine dentate gyrus (DG) promotes exploratory behavior, facilitates LTP in the medial perforant path, and enhances rapid-acquisition spatial memory. These phenotypes are reversed by a cell-permeant peptide (DNIP) designed to interfere with NCS-1 binding to D2R, and by D2R-selective antagonist L-741,626, placing NCS-1 action upstream of D2R in DG plasticity. Inducible transgenic overexpression in DG, LTP recording, behavioral testing, cell-permeant inhibitory peptide (DNIP), D2R antagonist Neuron High 19755107
2018 NCS-1 forms a complex with WFS1 (Wolframin) and the inositol 1,4,5-trisphosphate receptor (IP3R) at ER-mitochondria contact sites to promote Ca2+ transfer from ER to mitochondria. NCS-1 abundance is reduced in WFS1-null patient fibroblasts, which show reduced ER-mitochondria interactions and Ca2+ exchange; NCS-1 overexpression in these cells restores ER-mitochondria contacts, Ca2+ transfer, and rescues mitochondrial dysfunction. Co-immunoprecipitation (WFS1–NCS-1–IP3R complex), live-cell Ca2+ imaging, mitochondrial functional assays, NCS-1 overexpression rescue in patient fibroblasts Science signaling High 30352948
2014 NCS-1 interaction with D2-autoreceptors (dependent on Cav1.3 L-type Ca2+ channel activity and intracellular Ca2+) is required for the expression of non-desensitizing D2-autoreceptor responses in adult substantia nigra dopamine neurons. Pharmacological and genetic blockade of Cav1.3 activity, internal Ca2+, or NCS-1/D2R interaction prevents the acquisition of the sensitized D2-autoreceptor phenotype. Electrophysiology in brain slices (juvenile and adult mouse SN DA neurons), pharmacological tools (L-type Ca2+ channel blockers), genetic manipulation of Cav1.3, in vivo cocaine/L-DOPA paradigm Brain : a journal of neurology High 24934288
2014 Drosophila Ric8a (homolog of mammalian synembryn/Ric8a) binds to Frq2 (NCS-1 homolog) but not to the nearly identical Frq1; the differential residues R94 and T138 account for this binding specificity. Human NCS-1 and Ric8a reproduce this interaction. Frq2 negatively regulates Ric8a to control synapse number via a Frq2-Ric8a-Gαs pathway, while regulation of neurotransmitter release by Ric8a is independent of Frq2 binding. Crystallography of Frq2, site-directed mutagenesis of Frq1 (R94/T138 residues), genetic epistasis (trans-heterozygous combinations), co-immunoprecipitation, synapse counting, electrophysiology Journal of cell science High 25074811
2017 The crystal structure of NCS-1 bound to the small molecule FD44 (an aminophenothiazine) reveals that FD44 stabilizes a mobile C-terminal helix inside a hydrophobic crevice of NCS-1, thereby sterically impeding Ric8a interaction. FD44 inhibits NCS-1/Ric8a binding and restores normal synapse number and associative learning in a Drosophila fragile X syndrome (FXS) model. X-ray crystallography of NCS-1/FD44 complex, structure-function studies with analogs, Drosophila FXS behavioral rescue, synapse counting Proceedings of the National Academy of Sciences of the United States of America High 28119500
2023 NCS-1 binding and Gα binding to Ric-8A are mutually exclusive. NCS-1 induces a structural rearrangement in Ric-8A that traps it in a conformation inaccessible to casein kinase II-mediated phosphorylation, thereby negatively regulating Ric-8A GEF activity toward Gα. Increasing Ca2+ concentration restores nucleotide exchange activity, defining a Ca2+-regulated switch. High-resolution crystallographic data define the NCS-1/Ric-8A interface. In vitro reconstitution of NCS-1/Ric-8A complexes, GEF activity assay (guanine nucleotide exchange), X-ray crystallography, biochemical phosphorylation assay eLife High 38018500
2002 NCS-1 expressed in 3T3L1 adipocytes inhibits insulin-stimulated GLUT4 translocation through a phosphatidylinositol 4-kinase-dependent pathway. Expression of PI4K mimics the NCS-1 inhibitory effect, while co-transfection with an inactive PI4K mutant prevents NCS-1-induced inhibition of GLUT4 translocation. NCS-1 partially co-localizes with GLUT4-EGFP in the perinuclear region. Overexpression in 3T3L1 adipocytes, GLUT4 translocation assay, inactive PI4K dominant-negative mutant rescue, co-localization imaging The Journal of biological chemistry Medium 12011096
2009 Drosophila Frequenin (NCS-1 homolog) modulates Ca2+ entry through a functional interaction with the α1-subunit (cacophony) of voltage-gated Ca2+ channels to regulate neurotransmitter release and nerve-terminal growth. Frq-null mutants show impaired Ca2+ entry sufficient to account for reduced neurotransmitter release. This effect is independent of PI4Kbeta, as Frq gain-of-function phenotypes remain present in PI4Kbeta-null background. Genetic deletion (frq-null via site-specific recombination), trans-heterozygous epistasis (frq/cacophony), electrophysiology, PI4Kbeta-null background Journal of cell science High 19861494
2010 NCS-1 binds to the inositol 1,4,5-trisphosphate receptor (InsP3R) and increases InsP3R channel open probability and InsP3-dependent Ca2+ release in cardiomyocytes. Paclitaxel (Taxol) increases NCS-1 expression, which in turn enhances InsP3R activity and accelerates spontaneous Ca2+ oscillations. ShRNA-mediated knockdown of NCS-1 decreases InsP3R-dependent Ca2+ release. These effects are ryanodine receptor-independent. Single-channel patch-clamp (InsP3R), shRNA knockdown, live-cell Ca2+ imaging, pharmacological dissection (InsP3R inhibitor, ryanodine) Journal of molecular and cellular cardiology High 20801127
2019 NCS-1 binds to residues 66–110 on the suppressor domain of InsP3R type 1 (InsP3R1). Leu-89 in the hydrophobic pocket of NCS-1 is critical for this interaction; NCS-1 Leu-89 variants reduce Ca2+ signaling and cell survival in breast cancer cells. Overexpression of WT NCS-1 increases Ca2+ signaling and cell survival, while Leu-89 NCS-1 variants have the opposite effect. Protein docking, co-immunoprecipitation, blocking peptides, site-directed mutagenesis (Leu-89 variants), Ca2+ imaging, cell survival assay The Journal of biological chemistry High 31659121
2009 Mu-calpain cleaves NCS-1 within its N-terminal pseudoEF-hand domain. Loss of this pseudoEF-hand markedly decreases NCS-1's affinity for Ca2+ as measured by isothermal titration calorimetry (ITC), suggesting the pseudoEF-hand stabilizes the three functional EF-hands. This reduced Ca2+ affinity may render NCS-1 incapable of responding to Ca2+ changes in vivo and may explain altered Ca2+ signaling in the presence of paclitaxel. In vitro mu-calpain cleavage assay, N-terminal sequencing, MALDI mass spectrometry, isothermal titration calorimetry (ITC) Cell calcium High 19732951
2012 NCS-1 associates with adenosine A2A receptors in living cells, demonstrated by BRET and co-immunoprecipitation. NCS-1 binding modulates downstream A2A receptor intracellular signaling in a Ca2+-dependent manner. Bioluminescence resonance energy transfer (BRET), co-immunoprecipitation Frontiers in molecular neuroscience Medium 22529776
2007 NCS-1 directly interacts with ARF1, ARF3, ARF5, and ARF6 (but not ARF4) at different intracellular locations as shown by fluorescent protein fragment complementation in live HeLa cells. ARF1 (but not ARF5 or ARF6) enhances the stimulatory effect of PI4Kbeta on regulated exocytosis, indicating specificity in the ARF–NCS-1–PI4Kbeta regulatory axis. Fluorescent protein fragment complementation, photobleaching (FRAP), exocytosis assay Traffic (Copenhagen, Denmark) Medium 17555535
1999 NCS-1 immunoreactivity in rat brain is specifically localized to neuronal cell bodies and axons (not glial cells), with the most intense subcellular labeling associated with the membranes of the trans-Golgi apparatus, and also with neurofilament-rich axonal structures. This localization was established by electron-microscopic immunohistochemistry and double-labeling with neurofilament markers. Light and electron microscopic immunohistochemistry, double-labeling with neurofilament antibody, subcellular fractionation-level resolution Cell and tissue research Medium 10022960
2001 NCS-1 overexpression in AtT-20 (anterior pituitary) cells reduces CRF-41-stimulated ACTH secretion from intact cells, while in permeabilized cells NCS-1 overexpression increases Ca2+-, GTPγS-, and mastoparan-stimulated ACTH secretion. This indicates NCS-1 increases the releasable ACTH pool while inhibiting CRF-41 stimulus-secretion coupling. Stable transfection of AtT-20 cells, ACTH secretion assay in intact and permeabilized cells, pharmacological stimulation Molecular and cellular endocrinology Medium 11694341
2006 GST-pulldown from bovine brain identified several novel NCS-1 binding partners including ARF1, Ca2+-dependent activator protein for secretion 1 (CAPS1), cyclic nucleotide phosphodiesterase, vacuolar ATPase, AP1 and AP2 complexes, and type I TGF-β receptor, detected in the presence of 1 µM free Ca2+. Some interactions were NCS-1-specific (not shared with hippocalcin or neurocalcin delta). GST pulldown from bovine brain cytosol and membrane extracts (Ca2+-dependent), MALDI-MS and Western blotting Proteomics Low 16470652
2003 NCS-1 (frequenin) is expressed in adult mouse ventricular myocytes and co-localizes with Kv4.2 at the sarcolemma, suggesting it functions as an auxiliary Kv4 channel subunit in the heart, particularly in the immature heart where NCS-1 expression is highest. Immunoblot, immunocytochemistry co-localization in isolated neonatal mouse ventricular myocytes Pediatric research Low 12612193
2008 NCS-1 differentially modulates voltage-gated Ca2+ channels in growth cones versus somata of regenerating Lymnaea neurons. A dominant-negative C-terminal NCS-1 peptide selectively reduces peak and sustained Ca2+ current densities, slope conductance, and shifts reversal potential in growth cones, but has no significant effect on somatic Ca2+ channels. Whole-cell patch-clamp in growth cones and somata of identified neurons (Lymnaea PeA neurons), dominant-negative NCS-1 C-terminal peptide The European journal of neuroscience Medium 18279316
2009 A proteomic/Y2H screen identified NCS-1 binding partners including ARF1, PI4Kbeta, DAN, and PINK1. GST pulldown confirmed these interactions. Morpholino-mediated knockdown in zebrafish demonstrated essential roles for arf1, pi4kbeta, dan, and pink1 in semicircular canal formation, consistent with NCS-1 operating in a PI4Kbeta/ARF1 secretory pathway for vestibular development. Y2H screen, GST pulldown, morpholino knockdown in zebrafish, inner ear phenotyping BMC neuroscience Medium 19320994
2019 NCS-1 co-immunoprecipitates with the insulin receptor (IR) in adipocyte membranes. NCS-1-deficient adipocytes fail to upregulate IR in response to high-fat diet, and there is a direct correlation between NCS-1 and IR concentrations in the adipocyte membrane. Co-immunoprecipitation of NCS-1 with IR, NCS-1 KO mouse model, western blotting for IR expression Frontiers in molecular neuroscience Low 31001084
2015 In Langmuir lipid monolayer experiments, NCS-1 binds preferentially to phospholipids with phosphoethanolamine polar head groups and unsaturated fatty acyl chains. Ca2+ binding by the three EF-hand motifs leads to conformational change that alters membrane binding. The myristoyl group has weak influence on membrane binding, suggesting absence of a classical Ca2+-myristoyl switch; instead, myristoylation may have a structural role in NCS-1 folding. Langmuir lipid monolayer insertion assay, measurement of maximum insertion pressure and synergy parameters, Ca2+-free vs Ca2+-bound comparison Colloids and surfaces. B, Biointerfaces Low 26705828
2024 NCS-1 physically and functionally interacts with TRPA1 channel. NCS-1 and TRPA1 co-immunoprecipitate; NCS-1 overexpression increases TRPA1 expression at both protein and mRNA levels, and enhances TRPA1-dependent Ca2+ influx, current density, open probability, and conductance. These functional effects depend on PI3K signaling. Co-immunoprecipitation, electrophysiology (single-channel and whole-cell), Ca2+ imaging (Fura-2), qRT-PCR, western blot, PI3K pathway inhibition Journal of physiology and biochemistry Medium 38564162
2025 NCS-1 promotes D2R trafficking to the plasma membrane through active exocytosis in a Ca2+-dependent manner. FDA-approved drugs azilsartan medoxomil, atorvastatin, and vilazodone disrupt the NCS-1/D2R interaction, reducing D2R surface expression. Structural studies show these compounds target the NCS-1 hydrophobic crevice overlapping the D2R binding site and perturb the dynamics of regulatory helix H10. In vitro binding assays, cell-based D2R surface expression assay, structural studies (X-ray crystallography implied by 'structural studies'), drug screen of FDA-approved compounds Journal of medicinal chemistry Medium 41211723
2022 NCS1 overexpression via mRNA injection in wfs1ab zebrafish (Wolfram syndrome model) restores aberrant mitochondrial respiration and hyperlocomotion phenotype, confirming that NCS1 rescues mitochondrial activity downstream of WFS1 deficiency. mRNA injection in zebrafish, Seahorse metabolic analysis, behavioral assay (visual motor response, touch-escape) Molecular therapy. Methods & clinical development Medium 36320410
2010 NCS-1 overexpression in PC12 cells downregulates the cAMP/PKA pathway, resulting in decreased cAMP levels, reduced phospho-CREB (Ser133), and decreased total and phospho-DARPP-32 (Thr34), without altering D2 receptor levels or DARPP-32 phosphorylation at Thr75. Stable NCS-1 overexpression in PC12 cells, cAMP assay, western blot for phospho-CREB and phospho-DARPP-32 Cellular and molecular neurobiology Low 20838877
2021 NCS-1 knockout mice show reduced dendritic complexity and spine density in prefrontal cortex and dorsal hippocampus (Golgi-Cox staining), accompanied by deficits in memory acquisition. RNA sequencing of Ncs1-/- brain tissues reveals NCS-1 modulates gene expression related to neuronal morphology and development. NCS-1 KO mouse, Golgi-Cox staining, behavioral memory testing, RNA sequencing FASEB journal Medium 34499766
2018 NCS-1 overexpression in breast cancer cells (MCF-7 and MB-231) increases invasion and motility and decreases cell-matrix adhesion to collagen IV. NCS-1 preferentially localizes to the leading edge of migrating cells, and overexpression increases metastasis formation in a nude mouse xenograft model. Overexpression in breast cancer cell lines, invasion/motility assay, wound healing, 3D collagen migration, xenograft mouse model, immunofluorescence localization FASEB journal Medium 30592625
2024 NCS-1 binds Li+ ions at the EF-hand domains with submillimolar affinity (Kd ~223 µM). Li+ binding quenches Trp emission, stabilizes α-helical structure similarly to Ca2+, does not promote NCS-1 dimerization, and increases NCS-1 affinity for the D2R binding peptide (similar to Ca2+). Molecular dynamics simulations suggest Li+ is coordinated by four oxygen atoms from Asp/Glu sidechains and one carbonyl oxygen. Fluorescence spectroscopy, circular dichroism, MD simulation, affinity measurements for D2R peptide binding Journal of inorganic biochemistry Low 39447483

Source papers

Stage 0 corpus · 74 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Interaction with neuronal calcium sensor NCS-1 mediates desensitization of the D2 dopamine receptor. The Journal of neuroscience : the official journal of the Society for Neuroscience 178 12351722
2002 Up-regulation of neuronal calcium sensor-1 (NCS-1) in the prefrontal cortex of schizophrenic and bipolar patients. Proceedings of the National Academy of Sciences of the United States of America 172 12496348
2009 NCS-1 in the dentate gyrus promotes exploration, synaptic plasticity, and rapid acquisition of spatial memory. Neuron 162 19755107
2001 Interaction of neuronal calcium sensor-1 (NCS-1) with phosphatidylinositol 4-kinase beta stimulates lipid kinase activity and affects membrane trafficking in COS-7 cells. The Journal of biological chemistry 131 11526106
2018 ER-mitochondria cross-talk is regulated by the Ca2+ sensor NCS1 and is impaired in Wolfram syndrome. Science signaling 115 30352948
2014 Cav1.3 channels control D2-autoreceptor responses via NCS-1 in substantia nigra dopamine neurons. Brain : a journal of neurology 102 24934288
1996 Direct modulation of calmodulin targets by the neuronal calcium sensor NCS-1. Proceedings of the National Academy of Sciences of the United States of America 97 8799187
2008 Metabotropic glutamate receptor-mediated LTD involves two interacting Ca(2+) sensors, NCS-1 and PICK1. Neuron 91 19109914
1994 Cation binding and conformational changes in VILIP and NCS-1, two neuron-specific calcium-binding proteins. The Journal of biological chemistry 90 7806504
1999 Cellular and subcellular distribution of the calcium-binding protein NCS-1 in the central nervous system of the rat. Cell and tissue research 70 10022960
1995 Identification of neuronal calcium sensor (NCS-1) possibly involved in the regulation of receptor phosphorylation. Journal of receptor and signal transduction research 62 8903951
2009 Frequenin/NCS-1 and the Ca2+-channel alpha1-subunit co-regulate synaptic transmission and nerve-terminal growth. Journal of cell science 57 19861494
2010 Paclitaxel accelerates spontaneous calcium oscillations in cardiomyocytes by interacting with NCS-1 and the InsP3R. Journal of molecular and cellular cardiology 56 20801127
2013 GCY-8, PDE-2, and NCS-1 are critical elements of the cGMP-dependent thermotransduction cascade in the AFD neurons responsible for C. elegans thermotaxis. The Journal of general physiology 51 24081984
2018 NCS-1 is a regulator of calcium signaling in health and disease. Biochimica et biophysica acta. Molecular cell research 50 29746899
2006 Analysis of the interacting partners of the neuronal calcium-binding proteins L-CaBP1, hippocalcin, NCS-1 and neurocalcin delta. Proteomics 50 16470652
2015 Origin, diversification and substrate specificity in the family of NCS1/FUR transporters. Molecular microbiology 48 25712422
2012 Multiple roles for frequenin/NCS-1 in synaptic function and development. Molecular neurobiology 40 22396213
2007 Specificity, promiscuity and localization of ARF protein interactions with NCS-1 and phosphatidylinositol-4 kinase-III beta. Traffic (Copenhagen, Denmark) 37 17555535
2017 Interference of the complex between NCS-1 and Ric8a with phenothiazines regulates synaptic function and is an approach for fragile X syndrome. Proceedings of the National Academy of Sciences of the United States of America 36 28119500
2006 Interaction between variation in the D2 dopamine receptor (DRD2) and the neuronal calcium sensor-1 (FREQ) genes in predicting response to nicotine replacement therapy for tobacco dependence. The pharmacogenomics journal 34 16402081
1995 Distribution pattern of three neural calcium-binding proteins (NCS-1, VILIP and recoverin) in chicken, bovine and rat retina. The Histochemical journal 34 7591845
2012 NCS-1 associates with adenosine A(2A) receptors and modulates receptor function. Frontiers in molecular neuroscience 32 22529776
2008 Expression of neuronal calcium sensor-1 (NCS-1) is decreased in leukocytes of schizophrenia and bipolar disorder patients. Progress in neuro-psychopharmacology & biological psychiatry 32 19091302
2014 The guanine-exchange factor Ric8a binds to the Ca²⁺ sensor NCS-1 to regulate synapse number and neurotransmitter release. Journal of cell science 29 25074811
2012 FREQ-Seq: a rapid, cost-effective, sequencing-based method to determine allele frequencies directly from mixed populations. PloS one 29 23118913
2014 NCS-1 deficiency causes anxiety and depressive-like behavior with impaired non-aversive memory in mice. Physiology & behavior 28 24631552
2009 Proteomic and functional analysis of NCS-1 binding proteins reveals novel signaling pathways required for inner ear development in zebrafish. BMC neuroscience 28 19320994
2004 MGluRs regulate the expression of neuronal calcium sensor proteins NCS-1 and VILIP-1 and the immediate early gene arg3.1/arc in the hippocampus in vivo. Biochemical and biophysical research communications 26 15336574
2015 Self-directed exploration provides a Ncs1-dependent learning bonus. Scientific reports 25 26639399
2007 DARPP-32 and NCS-1 expression is not altered in brains of rats treated with typical or atypical antipsychotics. Neurochemical research 25 17763944
2017 Calcium Sensor, NCS-1, Promotes Tumor Aggressiveness and Predicts Patient Survival. Molecular cancer research : MCR 22 28275088
2003 Developmental expression of NCS-1 (frequenin), a regulator of Kv4 K+ channels, in mouse heart. Pediatric research 22 12612193
2002 NCS-1 inhibits insulin-stimulated GLUT4 translocation in 3T3L1 adipocytes through a phosphatidylinositol 4-kinase-dependent pathway. The Journal of biological chemistry 22 12011096
2005 Expression of the neuronal calcium sensor protein NCS-1 in the developing mouse olfactory pathway. The Journal of comparative neurology 19 15611992
2019 Characterization of NCS1-InsP3R1 interaction and its functional significance. The Journal of biological chemistry 18 31659121
2016 Cryptic purine transporters in Aspergillus nidulans reveal the role of specific residues in the evolution of specificity in the NCS1 family. Molecular microbiology 17 27741561
2018 Neuronal calcium sensor 1 (NCS1) promotes motility and metastatic spread of breast cancer cells in vitro and in vivo. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 16 30592625
2009 Discrete proteolysis of neuronal calcium sensor-1 (NCS-1) by mu-calpain disrupts calcium binding. Cell calcium 16 19732951
2008 NCS-1 differentially regulates growth cone and somata calcium channels in Lymnaea neurons. The European journal of neuroscience 16 18279316
2019 NCS-1 Deficiency Affects mRNA Levels of Genes Involved in Regulation of ATP Synthesis and Mitochondrial Stress in Highly Vulnerable Substantia nigra Dopaminergic Neurons. Frontiers in molecular neuroscience 14 31827421
2015 Membrane binding of Neuronal Calcium Sensor-1 (NCS1). Colloids and surfaces. B, Biointerfaces 14 26705828
2008 Methylphenidate alters NCS-1 expression in rat brain. Neurochemistry international 14 18514368
2010 Lack of effects of typical and atypical antipsychotics in DARPP-32 and NCS-1 levels in PC12 cells overexpressing NCS-1. Journal of negative results in biomedicine 13 20565907
2021 Neuronal calcium sensor 1 (NCS1) dependent modulation of neuronal morphology and development. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 11 34499766
2019 NCS-1 Deficiency Is Associated With Obesity and Diabetes Type 2 in Mice. Frontiers in molecular neuroscience 10 31001084
2014 Evaluation of NCS-1, DARPP-32, and neurotrophins in hippocampus and prefrontal cortex in rats submitted to sepsis. Synapse (New York, N.Y.) 10 24978930
2006 NCS-1 expression in rat brain after electroconvulsive stimulation. Neurochemical research 10 17160505
2022 NCS1 overexpression restored mitochondrial activity and behavioral alterations in a zebrafish model of Wolfram syndrome. Molecular therapy. Methods & clinical development 9 36320410
2019 NCS-1 expression is higher in basal breast cancers and regulates calcium influx and cytotoxic responses to doxorubicin. Molecular oncology 9 31647602
2008 Molecular characterization of the Aspergillus fumigatus NCS-1 homologue, NcsA. Molecular genetics and genomics : MGG 9 18830711
2004 Disruption of the NCS-1/frequenin-related ncsA gene in Dictyostelium discoideum accelerates development. Development, growth & differentiation 8 15606490
2010 Downregulation of the cAMP/PKA pathway in PC12 cells overexpressing NCS-1. Cellular and molecular neurobiology 7 20838877
2003 Identification and subcellular localization of neuronal calcium sensor-1 (NCS-1) in human neutrophils and HL-60 cells. Inflammation 7 14760944
2024 NCS-1 protein regulates TRPA1 channel through the PI3K pathway in breast cancer and neuronal cells. Journal of physiology and biochemistry 6 38564162
2020 Calcium Binding Protein Ncs1 Is Calcineurin Regulated in Cryptococcus neoformans and Essential for Cell Division and Virulence. mSphere 6 32907953
2015 Heterologous complementation studies reveal the solute transport profiles of a two-member nucleobase cation symporter 1 (NCS1) family in Physcomitrella patens. Plant physiology and biochemistry : PPB 6 26773540
2001 Over-expression of NCS-1 in AtT-20 cells affects ACTH secretion and storage. Molecular and cellular endocrinology 6 11694341
2021 Comprehensive somatosensory and neurological phenotyping of NCS1 knockout mice. Scientific reports 5 33504822
2020 Contribution of neuronal calcium sensor 1 (Ncs-1) to anxiolytic-like and social behavior mediated by valproate and Gsk3 inhibition. Scientific reports 5 32165725
2023 The neuronal calcium sensor NCS-1 regulates the phosphorylation state and activity of the Gα chaperone and GEF Ric-8A. eLife 4 38018500
2022 The inhibition of NCS-1 binding to Ric8a rescues fragile X syndrome mice model phenotypes. Frontiers in neuroscience 3 36466176
2023 Distinct mechanism of Tb3+ and Eu3+ binding to NCS1. Physical chemistry chemical physics : PCCP 2 36938969
2023 Generation of an NCS1 gene knockout human induced pluripotent stem cell line using CRISPR/Cas9. Stem cell research 2 37984032
2021 Foxp3 attenuates cerebral ischemia/reperfusion injury through microRNA-150-5p-modified NCS1. Experimental cell research 2 34822811
2016 Putative orotate transporter of Cryptococcus neoformans, Oat1, is a member of the NCS1/PRT transporter super family and its loss causes attenuation of virulence. Current genetics 2 28011993
2010 Inhibitory avoidance task does not change NCS-1 level in rat brain. Brain research bulletin 2 20493243
2026 Spinal overexpression of CAPN1 in CaMKII neurons mediates paclitaxel-induced neuropathic pain via NCS-1-TRPV4 signaling. Molecular pain 1 41482880
2025 The DLX1-NCS1-MYC axis drives oncogenesis and progression in lung adenocarcinoma. Biochimica et biophysica acta. Molecular basis of disease 1 40614386
2025 FDA Drug Repurposing Uncovers Modulators of Dopamine D2 Receptor Localization via Disruption of the NCS-1 Interaction. Journal of medicinal chemistry 1 41211723
2024 Substrate identification of putative NCS1 and NCS2 nucleobase transporters in Pseudomonas aeruginosa. mBio 1 39475230
2026 An AI-based approach accelerates the discovery of protein-protein interaction modulators targeting NCS-1. European journal of medicinal chemistry 0 41785832
2024 Interactions of Li+ ions with NCS1: A potential mechanism of Li+ neuroprotective action against psychotic disorders. Journal of inorganic biochemistry 0 39447483
2024 Stress survival and longevity of Caenorhabditis elegans lacking NCS-1. Toxicology research 0 39555232

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