Affinage

SLC24A2

Sodium/potassium/calcium exchanger 2 · UniProt Q9UI40

Length
661 aa
Mass
73.7 kDa
Annotated
2026-06-10
33 papers in source corpus 25 papers cited in narrative 25 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

SLC24A2 (NCKX2) is a plasma-membrane K+-dependent Na+/Ca2+ exchanger that serves as a principal Ca2+ extrusion mechanism in neurons, supporting Ca2+ homeostasis, synaptic plasticity, and neuroprotection (PMID:11342562, PMID:16407245). Electrophysiological reconstitution established that a single recombinant NCKX2 polypeptide transports with a stoichiometry of 4 Na+:(1 Ca2+ + 1 K+), with currents dependent on external Ca2+, K+, and Na+ (PMID:11342562). The protein adopts a 5+5 transmembrane topology with an extracellular C-terminus, distinguishing it from NCX exchangers (PMID:12600216, PMID:12377762). Systematic scanning mutagenesis of the α1 and α2 repeats defined a single shared cation-binding pocket centered on the acidic residues Glu188 and Asp548, with Asp575 uniquely conferring K+ dependence and Thr-551 tuning the low apparent K+ affinity; these residues line a common alternating-access pathway for Na+, Ca2+, and K+ (PMID:15583008, PMID:15611132, PMID:17172467, PMID:20231282). Transport is modulated by Na+-dependent inactivation and by PKC-mediated phosphorylation at sites including Thr-476 that enhances exchanger current (PMID:17164249, PMID:17038313). In neurons, NCKX2 surface polarization to axons requires KIF21A-mediated anterograde transport via interaction of the NCKX2 intracellular loop with the kinesin WD-40 domain, combined with selective somatodendritic clathrin-dependent endocytosis driven by a Tyr-365 YGKL motif binding the AP-2 µ subunit, which is itself negatively regulated by Src-family kinase phosphorylation (PMID:22442075, PMID:23431067). Loss of NCKX2 non-redundantly impairs hippocampal LTP, motor learning, and spatial working memory through reduced CaMKII/CaMKIV signaling, and NCKX2 limits ischemic Ca2+ overload to provide neuroprotection, including as an AKT-dependent effector of ischemic preconditioning (PMID:16407245, PMID:18305240, PMID:28547530, PMID:35806133).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2001 High

    Established that a single NCKX2 polypeptide is sufficient to encode a K+-dependent Na+/Ca2+ exchanger and defined its transport stoichiometry, answering whether NCKX activity required additional subunits.

    Evidence Whole-cell patch clamp of HEK293 cells expressing recombinant rat NCKX2 with ion-substitution reversal-potential measurements

    PMID:11342562

    Open questions at the time
    • Did not resolve the membrane topology or the molecular identity of ion-binding sites
    • No structural model of the transport pathway
  2. 2002 Medium

    Probed how disulfide chemistry and cysteine residues constrain NCKX2 structure, oligomerization, and surface expression, addressing the protein's quaternary organization.

    Evidence Site-directed mutagenesis, epitope-accessibility, biotin-maleimide labeling, and co-immunoprecipitation in HEK293 cells

    PMID:12377762

    Open questions at the time
    • Dimerization conclusion rests on a single co-IP
    • Functional role of redox-sensitive Cys-395 dimerization in vivo untested
  3. 2003 High

    Determined the membrane topology of NCKX2 and the disposition of its C-terminus, resolving how its architecture differs from related NCX exchangers and how it reaches the plasma membrane.

    Evidence Cysteine accessibility plus N-glycosylation site insertion for topology; signal-peptide cleavage and surface biotinylation analyses in heterologous cells

    PMID:12600216 PMID:12899631

    Open questions at the time
    • Topology inferred from accessibility, not direct structure
    • Signal-peptide work used Medium-confidence functional/biotinylation readouts
  4. 2004 High

    Identified the central acidic residues forming a single shared Ca2+/K+ binding pocket and the residue specifying K+ dependence, answering how one transport pathway accommodates both cations.

    Evidence Scanning and targeted site-directed mutagenesis with fluorometric Ca2+/K+-dependence assays in HEK293 cells; cysteine-free mutant with co-IP for oligomerization

    PMID:15196038 PMID:15583008 PMID:15611132

    Open questions at the time
    • Direct atomic positions of cations not yet visualized
    • Coupling mechanism of ion translocation not established
  5. 2005 Medium

    Mapped the three-dimensional proximity of the α1 and α2 repeats, establishing that the binding-pocket residues converge in space to form a shared cation site.

    Evidence Site-directed disulfide cross-linking and mobility-shift analysis of residue pairs in NCKX2 expressed in HEK293 cells

    PMID:15909993

    Open questions at the time
    • Proximity inferred from disulfide trapping, not a crystal structure
    • Conformational changes during transport not captured
  6. 2006 High

    Demonstrated the non-redundant physiological requirement for NCKX2 in neuronal Ca2+ homeostasis, synaptic plasticity, and behavior, moving from in vitro transport to organismal function.

    Evidence Constitutive NCKX2 knockout mice with cortical Ca2+ flux, LTP/LTD electrophysiology, and behavioral testing

    PMID:16407245

    Open questions at the time
    • Downstream signaling pathway not yet defined
    • Compensation by other NCKX/NCX isoforms not fully excluded
  7. 2006 Medium

    Defined acute regulatory mechanisms of NCKX2 activity — Na+-dependent inactivation and PKC-mediated phosphorylation — and refined affinity-determining residues, addressing how transport is dynamically tuned.

    Evidence Fluorometric and patch-clamp transport assays with gramicidin Na+ control, 32P labeling, dominant-negative PKCε, and site-directed mutagenesis; Ca2+ imaging at calyx of Held

    PMID:17038313 PMID:17164249 PMID:17172467

    Open questions at the time
    • Direct phosphorylation site mapping incomplete
    • Physiological triggers of inactivation in neurons not established
  8. 2008 High

    Established NCKX2 as a neuroprotective Ca2+ extruder limiting ischemic Ca2+ overload, linking exchanger loss to infarct severity.

    Evidence Antisense knockdown and knockout with in vivo MCAO, oxygen-glucose deprivation of cortical neurons, Ca2+ imaging, and patch-clamp current measurement

    PMID:18305240

    Open questions at the time
    • Upstream regulators controlling NCKX2 level during ischemia not yet identified
    • Therapeutic targetability not addressed
  9. 2012 High

    Identified the trafficking machinery establishing polarized axonal surface NCKX2, answering how the exchanger reaches axon terminals.

    Evidence Co-immunoprecipitation, dominant-negative and knockdown KIF21A, live-cell NCKX2-GFP imaging, and Ca2+ imaging at axonal boutons in rat hippocampal neurons

    PMID:22442075

    Open questions at the time
    • Structural basis of NCKX2 loop–KIF21A WD-40 interaction unknown
    • Regulation of motor loading not defined
  10. 2013 Medium

    Defined the endocytic arm of NCKX2 polarization through AP-2 recognition of a Tyr-365 motif and its negative regulation by Src-family kinases, completing the surface-targeting model.

    Evidence Co-IP, Y365A mutagenesis, AP2M1 knockdown, PP2 inhibition, and Ca2+ imaging in hippocampal and PC-12 cells

    PMID:23431067

    Open questions at the time
    • Not independently replicated
    • Identity of the responsible SFK and direct kinase–substrate relationship not pinned down
  11. 2015 Medium

    Resolved the subcellular distribution of native NCKX2 in adult hippocampus, situating the exchanger predominantly on dendritic plasma membrane with presynaptic and spine fractions.

    Evidence Dual immunofluorescence confocal and immunoelectron microscopy with compartmental markers in mouse hippocampus

    PMID:26410028

    Open questions at the time
    • Functional consequence of compartment-specific localization not directly tested here
    • Intracellular pool identity unclear
  12. 2016 Medium

    Provided a structure-based model rationalizing the experimentally defined cation-binding residues, assigning Asp575 to K+ and Asp548 to Ca2+ coordination.

    Evidence NCX_Mj-based homology modeling with molecular dynamics and free energy perturbation validated against prior mutagenesis

    PMID:27805378

    Open questions at the time
    • No experimental NCKX2 structure
    • Model is computational without new measurements
  13. 2018 High

    Generated comprehensive residue-level maps of the Na+, Ca2+, and K+ transport pathway across the α1/α2 repeats, consolidating the shared alternating-access pathway model.

    Evidence Exhaustive scanning mutagenesis of α1/α2 repeats with fluorometric Ca2+/K+-dependence assays mapped onto the homology model

    PMID:20231282 PMID:29960184 PMID:30173760

    Open questions at the time
    • Conformational dynamics of alternating access not directly observed
    • Structural assignments depend on the homology model
  14. 2020 Medium

    Identified microRNAs (miR-223-5p, miR-135a-5p) that directly repress SLC24A2, linking exchanger downregulation to ischemic injury and neuropathic pain and establishing therapeutic rescue.

    Evidence Luciferase 3'UTR reporter assays, in vivo MCAO and chronic-constriction-injury models with anti-miR infusion or SLC24A2 overexpression rescue

    PMID:31791013 PMID:32582988

    Open questions at the time
    • Single-lab findings for each miRNA
    • Cell-type specificity of miRNA repression not fully resolved
  15. 2022 Medium

    Placed NCKX2 within neuroprotective and addiction-related signaling, as an AKT-dependent effector of ischemic preconditioning and a regulator of prefrontal Ca2+ homeostasis in behavioral sensitization.

    Evidence Ischemic preconditioning with NCKX2 KO and AKT inhibition; AAV-mediated bidirectional NCKX2 manipulation in prefrontal cortex with methamphetamine sensitization paradigms

    PMID:35806133 PMID:36336087

    Open questions at the time
    • Mechanistic link between AKT and NCKX2 transcription/translation undefined
    • Single-lab behavioral findings
  16. 2017 Medium

    Positioned NCKX2-dependent Ca2+ signaling upstream of CaMKII/CaMKIV activation in the LTP pathway, connecting exchanger function to defined plasticity signaling cascades.

    Evidence Heterozygous NCKX2 knockout mice with immunoblotting of phospho-CaMKII/IV, GluA1, CREB, BDNF, and calcineurin activity, plus LTP and behavior

    PMID:28547530

    Open questions at the time
    • Causal directionality inferred from correlated phospho-changes
    • Not independently replicated

Open questions

Synthesis pass · forward-looking unresolved questions
  • A high-resolution experimental structure of NCKX2 capturing alternating-access conformational states, and the in vivo signaling that links upstream kinases (AKT, SFK, PKC) to NCKX2 abundance and trafficking, remain undefined.
  • No experimental atomic structure of NCKX2
  • Transition between inward- and outward-facing states not visualized
  • Mechanistic coupling of AKT-dependent NCKX2 upregulation unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 5 GO:0140104 molecular carrier activity 2
Localization
GO:0005886 plasma membrane 4
Pathway
R-HSA-112316 Neuronal System 2 R-HSA-382551 Transport of small molecules 2
Partners
AP2M1CNGAKIF21A

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 Electrophysiological characterization of rat brain NCKX2 heterologously expressed in HEK293 cells established a transport stoichiometry of 4 Na+:(1 Ca2+ + 1 K+), with outward currents depending on external Ca2+ (K1/2 ~1.4 µM without Mg2+) and external K+ (K1/2 ~12 mM), and inward currents depending on external Na+ (K1/2 ~30 mM, Hill coefficient 2.8), providing the first electrophysiological evidence that a single recombinant NCKX polypeptide encodes a K+-transporting Na+/Ca2+ exchanger. Whole-cell patch clamp of HEK293 cells expressing recombinant rat brain NCKX2; reversal potential measurements under altered individual ion gradients The Journal of biological chemistry High 11342562
2003 Topology mapping of NCKX2 using substituted-cysteine accessibility and insertion of N-glycosylation sites determined that both transmembrane segment sets each contain five membrane-spanning helices (not six), and the C-terminus is located extracellularly, differing from the NCX topology model. Site-directed mutagenesis introducing cysteines for accessibility assay; insertion of N-glycosylation sites; two independent topological methods applied to NCKX2 expressed in heterologous cells Biochemistry High 12600216
2002 Site-directed mutagenesis of NCKX2 revealed that Cys-614 and Cys-666 are required for protein expression in HEK-293 cells (but not in vitro), supporting an extracellular disulfide bond that stabilizes the structure and places the C-terminus extracellularly. Cys-395 in the large intracellular loop mediates redox-sensitive dimerization: a disulfide through Cys-395 reduces transport activity, and co-immunoprecipitation showed self-association of wild-type NCKX2 that was not prevented by Cys-395→Ala mutation. Site-directed mutagenesis; HA epitope tagging and antibody detection without permeabilization; biotin-maleimide labeling after extracellular β-mercaptoethanol; co-immunoprecipitation of wild-type and FLAG-tagged NCKX2 The Journal of biological chemistry Medium 12377762
2004 Scanning mutagenesis of candidate residues within NCKX2 transmembrane domains identified Glu188 and Asp548 as the central residues of a single cation binding pocket accommodating both Ca2+ and K+; charge-conservative substitutions of these residues caused the largest shifts in both K+ and Ca2+ dependences, whereas size-conservative substitutions yielded nonfunctional proteins. Additional residues (Pro187, Pro547, Asp258, Glu265, Glu533, Ser185, Ser545) showed smaller but coupled shifts in Ca2+ and K+ dependences, consistent with a single transport pathway for both ions. Site-directed mutagenesis; fluorometric assay for Ca2+ and K+ dependence in HEK293 cells expressing mutant NCKX2 The Journal of biological chemistry High 15583008
2004 Substitution of Asp575 to either Asn or Cys rendered NCKX2 independent of K+, while the charge-conservative Asp575→Glu substitution produced a nonfunctional exchanger. This identifies Asp575 as the critical residue specifying K+ dependence in NCKX, conserved in NCKX1–5 but replaced by Asn in K+-independent NCX exchangers. Site-directed mutagenesis of NCKX2 expressed in HEK293 cells; fluorometric Ca2+ transport assay measuring K+ dependence The Journal of biological chemistry High 15611132
2003 Signal peptide cleavage was found to occur for human (and chicken) cone NCKX2 expressed in HEK293 cells, and only the cleaved form was detected at the plasma membrane. Deletion of the signal sequence abolished plasma membrane targeting of NCKX2 as judged by loss of function and absence of surface biotinylation. Peptide tag insertion at multiple NCKX sequence positions; surface biotinylation; heterologous expression in HEK293 cells Biochemistry Medium 12899631
2005 Site-directed disulfide mapping showed that the α1 and α2 repeats of NCKX2 are in close three-dimensional proximity: Glu188Cys (α1) forms a disulfide with Asp548Cys (α2), and Ser185Cys forms disulfides with Ser545Cys, Asp548Cys, and Ser552Cys in α2. Asp575 was placed in proximity to Ser185 and Glu188, consistent with its role in K+ binding within the shared cation binding pocket. Site-directed disulfide mapping in NCKX2 expressed in HEK293 cells; crosslinking with oxidizing agents; mobility-shift analysis Biochemistry Medium 15909993
2006 NCKX2 knockout mice showed significant reduction in Ca2+ flux in cortical neurons, profound loss of hippocampal LTP, increase in LTD at Schaffer/CA1 synapses, and deficits in motor learning and spatial working memory, demonstrating a critical non-redundant role for NCKX2 in neuronal Ca2+ homeostasis and synaptic plasticity. No loss of cone photoreceptor function was detected despite reported cone expression. Constitutive knockout mouse; Ca2+ flux measurements in cortical neurons; electrophysiological recording of LTP/LTD; behavioral tests (motor learning, spatial working memory) The Journal of biological chemistry High 16407245
2006 Thr-551 in NCKX2 is a key residue determining the exchanger's low apparent K+ affinity: mutation of Thr-551 to Ala (the corresponding residue in NCKX4) shifted K+ affinity ~40-fold higher without parallel shift in Ca2+ affinity. The reciprocal NCKX4 mutation (Gln-476→Lys, corresponding to Lys in NCKX2) reduced both K+ and Ca2+ affinities, indicating Thr-551 acts within a structurally specific context in NCKX2. Site-directed mutagenesis; fluorometric functional assay in HEK293 cells expressing NCKX2, NCKX3, and NCKX4 mutants The Journal of biological chemistry High 17172467
2006 NCKX2 undergoes Na+-dependent inactivation: high intracellular Na+ combined with high extracellular Ca2+ occupancy promoted inactivation (t1/2 ~40 s) of NCKX2 transport in HEK293 cells. Two NCKX2 mutants with increased internal Na+ affinity (~19 mM) also displayed enhanced inactivation, indicating that binding of Na+ to intracellular transport sites is required for inactivation. Fluorometric Ca2+ transport assay in HEK293 cells using gramicidin to control intracellular Na+; site-directed mutagenesis identifying enhanced-inactivation mutants The Journal of biological chemistry Medium 17164249
2006 PKC activation by β-phorbol dibutyrate (PDBu) enhanced NCKX2 outward current in HEK293 cells in a PKC inhibitor-sensitive and alkaline phosphatase-sensitive manner. PDBu stimulated 32P incorporation into NCKX2. Double-site alanine mutations at Thr-476 (T166A/T476A and T476A/S504A) disrupted PKC-mediated enhancement, implicating multiple phosphorylation events. PKC activation also accelerated Ca2+ transient decay at the calyx of Held, where NCKX is the major Ca2+ clearance mechanism. Whole-cell patch clamp; 32P phosphorylation assay; dominant-negative PKCε overexpression; intracellular alkaline phosphatase perfusion; site-directed mutagenesis of PKC consensus sites; Ca2+ imaging at calyx of Held The Journal of biological chemistry Medium 17038313
2008 NCKX2 knockdown by antisense oligodeoxynucleotide and NCKX2 knockout both dramatically increased infarct volume in rat/mouse focal ischemia models. NCKX2-/- cortical neurons showed higher vulnerability and greater [Ca2+]i increase under oxygen-glucose deprivation, and forward and reverse NCKX currents were significantly reduced in NCKX2-/- neurons compared to wild-type, demonstrating a neuroprotective role for NCKX2 in ischemia through Ca2+ extrusion. Antisense oligodeoxynucleotide knockdown; constitutive knockout; permanent and transient MCAO in vivo; oxygen-glucose deprivation of primary cortical neurons; Ca2+ imaging; patch-clamp measurement of NCKX currents The Journal of neuroscience High 18305240
2010 Scanning mutagenesis of >100 NCKX2 residues identified 31 whose substitution shifted Na+ affinity, including the central acidic residues Glu188, Asp548, Asp575, their neighbors in the α1 and α2 repeats, and additional residues in transmembrane segment 3, supporting an alternating access model in which a shared set of residues lines the transport pathway for Na+, Ca2+, and K+. Site-directed mutagenesis; fluorometric Ca2+ transport assay in gramicidin-treated HEK293 cells to control intracellular Na+ The Journal of biological chemistry High 20231282
2012 NCKX2 is the first neuron-specific cargo molecule identified for kinesin motor KIF21A. The intracellular loop of NCKX2 specifically interacts with the WD-40 repeat domain (putative cargo-binding domain) of KIF21A. Dominant-negative KIF21A or KIF21A depletion blocked NCKX2-GFP transport to axon fibers and caused calcium dysregulation at axonal boutons but not somatodendritic regions. Additionally, constitutive somatodendritic endocytosis (via clathrin) maintains the polarized axonal surface expression of NCKX2: inhibition of endocytosis increased somatodendritic surface NCKX2 and abolished axonal polarization. Co-immunoprecipitation; dominant-negative KIF21A expression; KIF21A knockdown; live-cell imaging of NCKX2-GFP; calcium imaging at axonal boutons; endocytosis inhibition assays in rat hippocampal neurons The Journal of neuroscience High 22442075
2013 Somatodendritic endocytosis of NCKX2 is mediated by interaction of the YGKL motif (Tyr-365) in the NCKX2 cytoplasmic loop with the AP-2 µ subunit (AP2M1), as shown by co-immunoprecipitation and requirement of Tyr-365 for this interaction. NCKX2-Y365A mutant or AP2M1 knockdown reduced somatodendritic internalization and abolished axonal polarization of surface NCKX2. Src family kinase (SFK)-dependent phosphorylation of Tyr-365 negatively regulates endocytosis: carbachol-induced phosphorylation was blocked by PP2 (SFK inhibitor), and PP2 facilitated NCKX2 endocytosis and suppressed NCKX activity in proximal dendrites. Co-immunoprecipitation; site-directed mutagenesis (Y365A); AP2M1 knockdown; live-cell immunocytochemistry in hippocampal neurons; PC-12 cell phosphorylation assay; PP2 pharmacological inhibition; Ca2+ imaging of NCKX activity Frontiers in cellular neuroscience Medium 23431067
2015 Immunofluorescence confocal microscopy and immunoelectron microscopy of adult mouse hippocampus showed that the majority of NCKX2 co-localizes with the dendritic marker MAP2 on the plasma membrane of small oblique dendrites in CA1 stratum radiatum neurons, with smaller fractions co-localizing with the presynaptic marker synapsin 1 and the glutamatergic spine marker NR1. A fraction of NCKX2 was found intracellularly (not plasma membrane-associated) in CA1 neurons. Dual immunofluorescent confocal microscopy; immunoelectron microscopy; co-localization with sub-compartmental markers in adult mouse hippocampus Neuroscience Medium 26410028
2016 A homology model of NCKX2 based on the archaeal NCX_Mj crystal structure, validated by molecular dynamics and free energy perturbation, identified that K+ binding is accomplished principally via Asp575 and Ca2+ binding via Asp548 in the active site lined with acidic and polar residues. Mutation D548N or D575N eliminates favorable carboxylate–cation interactions and alters transport function, consistent with experimental data. Homology modelling based on NCX_Mj crystal structure; molecular dynamics simulations; free energy perturbation calculations; validation against published mutagenesis data Biochemistry Medium 27805378
2017 NCKX2 heterozygous mice showed decreased CaMKII autophosphorylation and CaMKIV phosphorylation in hippocampal CA1, with reduced phosphorylation of downstream targets GluA1 (Ser-831) and CREB (Ser-133), decreased BDNF protein and mRNA, and increased calcineurin (CaN) activity, alongside impaired hippocampal LTP and memory acquisition, placing NCKX2-dependent Ca2+ signaling upstream of CaMKII/IV activation in the LTP pathway. Constitutive NCKX2 heterozygous knockout mice; immunoblotting for phospho-CaMKII, phospho-CaMKIV, phospho-GluA1, phospho-CREB; BDNF ELISA; CaN activity assay; LTP electrophysiology; behavioral tasks Molecular neurobiology Medium 28547530
2018 Scanning mutagenesis of all residues in the α1 and α2 repeats of NCKX2 (93 substitutions) identified 31 residues shifting external Ca2+ dependence; 13 with decreased affinity were mapped to direct Ca2+ contact or lining of a Ca2+ transport pathway using the NCX_Mj crystal structure-based homology model. Site-directed mutagenesis; fluorescent intracellular Ca2+-indicating dye assay in HEK293 cells; comparison with NCX_Mj crystal structure homology model Cell calcium Medium 30173760
2018 Scanning mutagenesis of all α1 and α2 repeat residues of NCKX2 identified 34 residues shifting external K+ dependence (16 increased affinity, 18 decreased affinity) and 8 residues whose substitution caused partial loss of K+ dependence, providing a comprehensive map of residues important for K+ transport and supporting cation binding sites identified in the NCX_Mj-based homology model. Site-directed mutagenesis; fluorescent intracellular Ca2+-indicating dye assay measuring K+ dependence in HEK293 cells; comparison with NCKX2 homology model Cell calcium Medium 29960184
2019 miR-223-5p directly targets the 3' UTR of the NCKX2/SLC24A2 transcript (subregion +7037 to +8697) as shown by luciferase reporter assay, and its expression increases in ischemic striatum in parallel with NCKX2 downregulation. Intracerebroventricular infusion of anti-miR-223-5p prevented NCKX2 downregulation after ischemia and reduced infarct volume. Luciferase reporter assay with NCKX2 3' UTR; transfection of cortical neurons with miR-223-5p; intracerebroventricular anti-miR-223-5p infusion in rat MCAO model; infarct volume measurement Molecular therapy. Nucleic acids Medium 31791013
2020 miR-135a-5p directly targets the 3' UTR of SLC24A2/NCKX2 transcript as shown by luciferase reporter assay; miR-135a-5p increases after sciatic nerve chronic constriction injury (CCI) in parallel with NCKX2 downregulation in spinal cord dorsal horn. Overexpression of SLC24A2 in CCI rats reduced mechanical and thermal hyperalgesia and decreased inflammatory cytokines (IL-1β, IL-6, TNF-α), and the anti-nociceptive effect of miR-135a-5p inhibition was SLC24A2-dependent. CCI neuropathic pain model in rats; luciferase reporter assay; behavioral tests (mechanical and thermal thresholds); miR-135a-5p inhibitor treatment; SLC24A2 overexpression rescue experiments; cytokine measurements Molecular medicine reports Medium 32582988
2022 NCKX2 acts as an effector of ischemic preconditioning-induced neuroprotection: NCKX2 expression increased in brain regions protected by preconditioning in a p-AKT-dependent manner (AKT inhibition prevented NCKX2 upregulation), and NCKX2 knockout significantly abolished the neuroprotection afforded by ischemic preconditioning. Ischemic preconditioning mouse model; NCKX2 knockout; AKT inhibitor treatment; Western blotting for NCKX2 and p-AKT; infarct volume measurement International journal of molecular sciences Medium 35806133
2022 AAV-mediated overexpression of NCKX2 in the prefrontal cortex attenuated the expression phase of methamphetamine-induced behavioral sensitization, while AAV-mediated knockdown enhanced it, demonstrating a role for NCKX2-dependent Ca2+ homeostasis in prefrontal cortex in METH-induced sensitization. NCKX2 levels were specifically decreased in prefrontal cortex and nucleus accumbens of behaviorally sensitized (but not CPP) mice. AAV-mediated overexpression and knockdown in mouse prefrontal cortex; METH-induced behavioral sensitization and conditioned place preference paradigms; Western blotting Neuroscience letters Medium 36336087
2004 A functional cysteine-free NCKX2 mutant protein was generated that showed normal synthesis and processing with ~50% wild-type cation transport function, demonstrating that no individual cysteine is absolutely required for NCKX2 transport activity. Cysteine residues were also not required for NCKX2 homo-oligomerization or for hetero-oligomer formation with the CNGA subunit of the cGMP-gated channel, as shown by co-immunoprecipitation. Site-directed mutagenesis generating cysteine-free NCKX2; Ca2+ transport functional assay; co-immunoprecipitation of NCKX2 with CNGA subunit Biochemistry Medium 15196038

Source papers

Stage 0 corpus · 33 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Importance of K+-dependent Na+/Ca2+-exchanger 2, NCKX2, in motor learning and memory. The Journal of biological chemistry 72 16407245
2001 Electrophysiological characterization and ionic stoichiometry of the rat brain K(+)-dependent NA(+)/CA(2+) exchanger, NCKX2. The Journal of biological chemistry 51 11342562
2006 Exchangers NCKX2, NCKX3, and NCKX4: identification of Thr-551 as a key residue in defining the apparent K(+) affinity of NCKX2. The Journal of biological chemistry 43 17172467
2003 Topology of the retinal cone NCKX2 Na/Ca-K exchanger. Biochemistry 43 12600216
2004 Residues contributing to the Ca2+ and K+ binding pocket of the NCKX2 Na+/Ca2+-K+ exchanger. The Journal of biological chemistry 36 15583008
2008 A critical role for the potassium-dependent sodium-calcium exchanger NCKX2 in protection against focal ischemic brain damage. The Journal of neuroscience : the official journal of the Society for Neuroscience 35 18305240
2004 Substitution of a single residue, Asp575, renders the NCKX2 K+-dependent Na+/Ca2+ exchanger independent of K+. The Journal of biological chemistry 34 15611132
2012 KIF21A-mediated axonal transport and selective endocytosis underlie the polarized targeting of NCKX2. The Journal of neuroscience : the official journal of the Society for Neuroscience 30 22442075
2019 Anti-miR-223-5p Ameliorates Ischemic Damage and Improves Neurological Function by Preventing NCKX2 Downregulation after Ischemia in Rats. Molecular therapy. Nucleic acids 29 31791013
2002 A novel topology and redox regulation of the rat brain K+-dependent Na+/Ca2+ exchanger, NCKX2. The Journal of biological chemistry 29 12377762
2015 Cation dependencies and turnover rates of the human K⁺-dependent Na⁺-Ca²⁺ exchangers NCKX1, NCKX2, NCKX3 and NCKX4. Cell calcium 26 26631410
2003 Signal sequence cleavage and plasma membrane targeting of the retinal rod NCKX1 and cone NCKX2 Na+/Ca2+ - K+ exchangers. Biochemistry 23 12899631
2017 Reduced CaM Kinase II and CaM Kinase IV Activities Underlie Cognitive Deficits in NCKX2 Heterozygous Mice. Molecular neurobiology 20 28547530
2010 Residues contributing to the Na(+)-binding pocket of the SLC24 Na(+)/Ca(2+)-K(+) Exchanger NCKX2. The Journal of biological chemistry 20 20231282
2016 Characterization of the Cation Binding Sites in the NCKX2 Na+/Ca2+-K+ Exchanger. Biochemistry 19 27805378
2006 Na+-dependent inactivation of the retinal cone/brain Na+/Ca2+-K+ exchanger NCKX2. The Journal of biological chemistry 19 17164249
2006 Protein kinase C-dependent enhancement of activity of rat brain NCKX2 heterologously expressed in HEK293 cells. The Journal of biological chemistry 16 17038313
2020 A critical role for miR‑135a‑5p‑mediated regulation of SLC24A2 in neuropathic pain. Molecular medicine reports 14 32582988
2005 Site-directed disulfide mapping of residues contributing to the Ca2+ and K+ binding pocket of the NCKX2 Na+/Ca2+-K+ exchanger. Biochemistry 14 15909993
2022 K+-Dependent Na+/Ca2+ Exchanger Isoform 2, Nckx2, Takes Part in the Neuroprotection Elicited by Ischemic Preconditioning in Brain Ischemia. International journal of molecular sciences 11 35806133
2018 Residues important for Ca2+ ion transport in the neuronal K+-dependent Na+-Ca2+ exchanger (NCKX2). Cell calcium 10 30173760
2013 Endocytosis of somatodendritic NCKX2 is regulated by Src family kinase-dependent tyrosine phosphorylation. Frontiers in cellular neuroscience 10 23431067
2018 Residues important for K+ ion transport in the K+-dependent Na+-Ca2+ exchanger (NCKX2). Cell calcium 9 29960184
2004 Role of cysteine residues in the NCKX2 Na+/Ca(2+)-K+ Exchanger: generation of a functional cysteine-free exchanger. Biochemistry 8 15196038
2015 Anatomical evidence for a non-synaptic influence of the K+ -dependent Na+/Ca2+ -exchanger, NCKX2, on hippocampal plasticity. Neuroscience 7 26410028
2007 Structure-function relationships of the NCKX2 Na+/Ca2+-K+ exchanger. Annals of the New York Academy of Sciences 6 17303823
2007 Involvement of the potassium-dependent sodium/calcium exchanger gene product NCKX2 in the brain insult induced by permanent focal cerebral ischemia. Annals of the New York Academy of Sciences 6 17446491
2022 Multiomics Integrated Analysis Identifies SLC24A2 as a Potential Link between Type 2 Diabetes and Cancer. Journal of diabetes research 5 35601016
2022 The roles of K+-dependent Na+/Ca2+ exchanger 2 (NCKX2) in methamphetamine-induced behavioral sensitization and conditioned place preference in mice. Neuroscience letters 4 36336087
2017 A SLC24A2 Gene Variant Uncovered in Pancreatic Ductal Adenocarcinoma by Whole Exome Sequencing. The Tohoku journal of experimental medicine 4 28413183
2007 Ionic selectivity of NCKX2, NCKX3, and NCKX4 for monovalent cations at K+-binding site. Annals of the New York Academy of Sciences 4 17446453
2007 Topologic investigation of the NCKX2 Na+/Ca2+-K+ exchanger alpha-repeats. Annals of the New York Academy of Sciences 1 17332073
2026 Nrf2 Protects Against Lipoteichoic Acid-Induced Acute Lung Injury By Suppressing SLC24A2-Mediated Ferroptosis. Inflammation 0 42104193

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