Affinage

FXYD1

Phospholemman · UniProt O00168

Length
92 aa
Mass
10.4 kDa
Annotated
2026-06-14
40 papers in source corpus 23 papers cited in narrative 23 extracted findings
Cross-family judge vs UniProt: Affinage preferred

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FXYD1 (phospholemman, PLM) is a single-span sarcolemmal protein that serves as the central regulatory hub coupling intracellular signaling to Na+ and Ca2+ homeostasis in cardiac, skeletal, and vascular tissue by tuning the activity of the Na/K-ATPase (NKA) and the Na+/Ca2+ exchanger NCX1 (PMID:16100047, PMID:17095720, PMID:17446450). PLM physically associates with NKA alpha1, alpha2, and alpha3 isoforms through its transmembrane domain, forming 1:1 complexes, and in its unphosphorylated state tonically inhibits the pump; its cytoplasmic C-terminal tail carries the regulatory phosphosites Ser-63 and Ser-68, where PKC phosphorylates both and PKA phosphorylates only Ser-68 (PMID:7999001, PMID:12657675, PMID:19638348). Phosphorylation at either Ser-63 or Ser-68 is necessary and sufficient to relieve PLM-mediated inhibition: PKA-driven Ser-68 phosphorylation raises the apparent Na+ affinity of both alpha1 and alpha2 isozymes, while PKC additionally increases Vmax selectively for alpha2, and these phosphorylation events reduce the physical NKA–PLM interaction (PMID:16943195, PMID:17991751, PMID:20861470). The same C-terminal tail allows Ser-68-phosphorylated PLM to inhibit NCX1, establishing PLM as a coordinator of pump and exchanger activity (PMID:17446450). PLM exists as both NKA-associated monomers and a separate pool of oligomers (≥3 monomers) that do not regulate the pump, with transmembrane residue L30 governing tetramerization (PMID:23532852, PMID:27718550), and its surface trafficking requires co-expression with NKA (PMID:22535957). Beyond phosphorylation, PLM is regulated by palmitoylation, which inhibits NKA and is reversed by a glutathione-dependent peroxiredoxin 6 thioesterase reaction (PMID:38236777), and nitric oxide activates NKA through a PKCε–PLM phosphorylation cascade (PMID:23612119). Genetic abolition of PLM phosphorylation causes Na+ overload, impaired NCX, exacerbated cardiac hypertrophy after pressure overload, enhanced vascular constriction, and hypertension, and a human R70C coding variant that blocks Ser-68 phosphorylation associates with elevated blood pressure (PMID:25103111, PMID:33334125).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1994 High

    Established the phosphorylation code of PLM by mapping which kinases target which cytoplasmic serines, the foundation for all later regulatory models.

    Evidence In vitro kinase assays with synthetic peptides plus phosphopeptide mapping of labeled PLM from rat diaphragm

    PMID:7999001

    Open questions at the time
    • Did not define the functional consequence of phosphorylation on any transporter
    • Did not identify the binding partner regulated by these sites
  2. 1995 Medium

    Provided the first functional readout of PLM by showing it induces ion currents in a heterologous system, framing it as a channel or channel regulator before its NKA role was known.

    Evidence Xenopus oocyte expression with electrophysiological current recording

    PMID:7836447

    Open questions at the time
    • Whether PLM forms the conductive pore or regulates an endogenous oocyte channel was unresolved
    • No link yet to NKA or NCX
  3. 1998 High

    Defined PLM membrane topology and localized voltage-dependent inactivation to the cytoplasmic tail, connecting structure to channel behavior.

    Evidence Protease protection, site-specific antibodies, and lipid bilayer electrophysiology with truncated PLM

    PMID:9486665

    Open questions at the time
    • Channel activity in bilayers not reconciled with a physiological transporter target
    • Cytoplasmic tail's later regulatory partners not yet identified
  4. 2000 Medium

    Extended the kinase repertoire acting on PLM and showed phosphorylation alters its membrane level and current, hinting at trafficking control.

    Evidence In vitro DMPK kinase assay and oocyte co-expression with phosphorylation-null PLM mutant

    PMID:10811636

    Open questions at the time
    • Physiological relevance of DMPK–PLM in heart not established
    • Mechanism linking phosphorylation to membrane level unclear
  5. 2001 Medium

    Demonstrated a physiological loss-of-function role for PLM in cell volume regulation via taurine efflux, broadening its functional reach beyond cardiac myocytes.

    Evidence Antisense knockdown in cerebellar astrocytes with tracer efflux assays

    PMID:11336802

    Open questions at the time
    • Molecular identity of the taurine-permeable pathway not defined
    • Relationship between volume regulation and NKA association unknown
  6. 2003 High

    Identified the Na/K-ATPase as a direct physical and functional partner of PLM, the discovery that reframed PLM as an NKA regulatory subunit.

    Evidence Co-purification and reciprocal Co-IP from cerebellum and choroid plexus with antibody-inhibition NKA activity assay

    PMID:12657675

    Open questions at the time
    • Whether PLM inhibits or activates NKA, and the role of phosphorylation, not yet resolved
    • Cardiac relevance untested
  7. 2005 Medium

    Confirmed the PLM–NKA association in cardiac and skeletal muscle and linked PLM dysregulation to heart failure, giving the interaction disease context.

    Evidence Co-IP from cardiac and skeletal muscle with NKA activity assays and phospho-Ser-68 immunoblotting

    PMID:15961612 PMID:16100047

    Open questions at the time
    • Causality of PLM changes in heart failure not established
    • Quantitative effect of phosphorylation on pump kinetics undefined
  8. 2006 High

    Resolved the directionality and mechanism of PLM regulation: PLM inhibits NKA, and phosphorylation relieves inhibition by reducing physical interaction, dissected by isoform-specific kinetics and genetic deletion.

    Evidence FRET in HEK293 cells plus whole-cell clamp and SBFI in PLM-knockout myocytes with PKA/PKC activation

    PMID:16943195 PMID:17095720

    Open questions at the time
    • Whether PLM dissociates or only reorients upon phosphorylation not fully resolved
    • NCX1 regulation not yet addressed
  9. 2007 High

    Defined the isozyme-specific kinetic logic (PKA raises Na+ affinity; PKC raises alpha2 Vmax) and revealed that phosphorylated PLM separately inhibits NCX1 through its cytoplasmic tail, establishing dual transporter control.

    Evidence Oocyte expression of defined NKA isozymes with mutants; Co-IP, NCX1 electrophysiology and 45Ca2+ uptake in cardiomyocytes and HEK293 cells

    PMID:17446450 PMID:17991751

    Open questions at the time
    • Structural basis of the opposite phospho-dependence for NKA versus NCX1 unexplained
    • Stoichiometry of NKA–PLM complex not yet measured
  10. 2009 High

    Established the stoichiometry of regulation, showing 1:1 NKA–PLM complexes for both alpha isoforms alongside PLM oligomers, refining the molecular model of pump regulation.

    Evidence Progressive acceptor-photobleach FRET in HEK293 cells and isoform-specific ouabain knock-in myocytes with clamp and SBFI

    PMID:19638348

    Open questions at the time
    • Functional role of the PLM oligomer pool not yet defined
    • How monomer/oligomer balance is controlled unknown
  11. 2010 High

    Showed phosphorylation of either Ser-63 or Ser-68 alone fully relieves NKA inhibition, defining the minimal molecular switch and explaining redundancy between PKA and PKC inputs.

    Evidence Single and double phosphosite mutants expressed with NKA-alpha1 in HeLa cells with SBFI readout

    PMID:20861470

    Open questions at the time
    • Whether the two sites are functionally equivalent in vivo not addressed
    • Structural mechanism of relief not resolved
  12. 2012 Medium

    Identified NKA as the obligate chaperone for PLM surface delivery, explaining how complex assembly is coupled to trafficking.

    Evidence Surface biotinylation in Xenopus oocytes with co-expression and trafficking mutants

    PMID:22535957

    Open questions at the time
    • Trafficking determinants in native cardiac cells not validated
    • Role of C-terminal arginine retention signal mechanistically unclear
  13. 2013 High

    Distinguished two physically and functionally distinct PLM pools (NKA-associated monomers versus non-regulatory oligomers), defined the NO–PKCε–PLM activation cascade, and began mapping the interaction surfaces with NKA and NCX1.

    Evidence Phosphospecific Co-IP, MS, cross-linking and transgenic hearts; NO/PKCε pathway dissection in PLM-WT/KO/3SA myocytes; domain mapping summarized in review

    PMID:23224879 PMID:23532852 PMID:23612119

    Open questions at the time
    • Why Ser-63-phosphorylated PLM partitions to oligomers is unknown
    • Domain-mapping details for the NCX1 interface rest on summarized rather than full primary data
  14. 2014 High

    Provided in vivo causality that PLM phosphorylation maintains NKA activity and limits Na+ overload and adverse remodeling under pressure overload.

    Evidence PLM-3SA knock-in mice with aortic constriction, echocardiography, pressure-volume catheterization, SBFI, and NKA current clamp

    PMID:25103111

    Open questions at the time
    • Relative contributions of NKA versus NCX dysregulation to remodeling not separated
    • Therapeutic reversibility not tested
  15. 2016 Medium

    Linked PLM tetramerization to its inhibitory potency by identifying L30 as a residue whose mutation destabilizes oligomers and superinhibits NKA, connecting oligomeric state to function.

    Evidence TM scanning mutagenesis with FRET, cardiomyocyte Ca2+ transients, and molecular dynamics simulations

    PMID:27718550

    Open questions at the time
    • Physiological regulation of PLM oligomeric state in vivo unknown
    • Single-lab finding without independent structural confirmation
  16. 2020 High

    Extended PLM regulation to vascular tone and human blood pressure, with a coding variant blocking Ser-68 phosphorylation, establishing translational relevance.

    Evidence PLM-3SA mice with wire myography and in vivo BP; HEK293 phosphorylation assay of R70C; UK Biobank and GoDARTS cohort analyses

    PMID:33334125

    Open questions at the time
    • Whether R70C is causal versus associated in humans not proven
    • Vascular cell type mediating the effect not pinpointed
  17. 2024 High

    Added a redox-coupled regulatory layer by identifying Prdx6 as a glutathione-dependent depalmitoylase that reverses inhibitory PLM palmitoylation of NKA.

    Evidence Co-IP, acyl-RAC, glutathione manipulation, Prdx6 silencing, in vitro depalmitoylation with recombinant proteins, palmostatin B, and NKA activity assays

    PMID:38236777

    Open questions at the time
    • Palmitoylating enzyme for PLM not identified
    • In vivo physiological role of PLM palmitoylation cycling untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple PLM regulatory inputs (phosphorylation, palmitoylation, glutathionylation, oligomerization) are integrated and prioritized to set Na+/Ca2+ homeostasis in a given physiological state remains unresolved.
  • No unified structural model of the NKA–PLM–NCX1 regulatory module
  • Crosstalk between palmitoylation and phosphorylation switches unmapped
  • Tissue-specific differences in PLM regulation not systematically compared

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-382551 Transport of small molecules 3
Partners
ATP1A1ATP1A2ATP1A3DMPKPRDX6PRKCESLC8A1
Complex memberships
Na/K-ATPase regulatory complex (FXYD1–NKA)

Evidence

Reading pass · 23 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 Protein kinase C phosphorylates phospholemman at both Ser-63 and Ser-68 in its cytoplasmic C-terminal domain, while cAMP-dependent protein kinase (PKA) phosphorylates only Ser-68. Insulin stimulation results in labeling of phosphopeptides containing both Ser-63 and Ser-68, whereas adrenaline results in labeling of the peptide containing Ser-68. In vitro phosphorylation assay with synthetic peptide substrates, amino acid sequencing of phosphopeptides, thermolytic phosphopeptide mapping of 32P-labeled phospholemman from rat diaphragm The Biochemical journal High 7999001
1995 Phospholemman (PLM) induces hyperpolarization-activated chloride currents when expressed in Xenopus oocytes, establishing it as a Cl- channel or Cl- channel regulator. Xenopus oocyte expression system with electrophysiological current recording The Journal of biological chemistry Medium 7836447
1998 PLM topology places the extracellular N-terminal segment (residues 1–17) in a protease-resistant configuration, while the intracellular C-terminal domain (residues 38–72) is protease-sensitive. The cytoplasmic tail is required for voltage-dependent channel inactivation: trypsin treatment yielding a limit peptide (residues 1–43) or recombinant PLM 1–43 retains ion-channel activity in lipid bilayers but shows dramatically reduced voltage-dependent inactivation. Protease protection assays on sarcolemmal membrane vesicles; site-specific antibody immunoblots; lipid bilayer electrophysiology with full-length, trypsinized, and recombinant truncated PLM Circulation research High 9486665
1999 PKA co-expression increases PLM-induced oocyte current amplitude and membrane PLM level largely through phosphorylation of Ser-68; a phosphorylation-null PLM mutant (SSST→AAAA) is unresponsive to PKA co-expression. The cytoplasmic domain is not essential for inducing currents. Xenopus oocyte co-expression with PKA, PKC, and NIMA kinase; electrophysiology; phosphorylation-site mutagenesis (Ser→Ala) Biochimica et biophysica acta Medium 10556585
2000 Phospholemman is a substrate for myotonic dystrophy protein kinase (DMPK) in vitro. Co-expression of DMPK with PLM in Xenopus oocytes reduces PLM-induced Cl- current amplitude and reduces membrane PLM expression; this effect is absent with a phosphorylation-null PLM mutant (all Ser→Ala), indicating it is phosphorylation-dependent. In vitro kinase assay; Xenopus oocyte co-expression; electrophysiology; phosphorylation-null PLM mutant The Journal of biological chemistry Medium 10811636
2001 Reduction of PLM expression by antisense oligonucleotides in cerebellar astrocytes decreases osmosensitive taurine efflux by 62–67%, demonstrating that PLM plays a role in regulatory volume decrease (RVD) via taurine flux. PKA activation increases this taurine efflux, while PKC appears largely dispensable for the taurine component. Antisense oligonucleotide knockdown of PLM in cerebellar astrocytes; [3H]taurine and 125I efflux assays; pharmacological PKA/PKC activation and inhibition Biochimica et biophysica acta Medium 11336802
2003 Phospholemman physically associates with Na,K-ATPase (all three alpha isoforms, alpha1–alpha3) in cerebellum and choroid plexus, demonstrated by co-purification and reciprocal co-immunoprecipitation. Antibodies against the C-terminal domain of PLM reduce Na,K-ATPase activity in vitro without altering Na+ affinity. Detergent co-purification; reciprocal co-immunoprecipitation from solubilized crude membranes; in vitro Na,K-ATPase activity assay with antibody inhibition The Journal of neuroscience High 12657675
2005 PLM co-immunoprecipitates with Na,K-ATPase alpha1 and alpha2 isoforms in cardiac myocytes; PLM expression is reduced in heart failure and a higher fraction of PLM is phosphorylated at Ser-68 in HF, consistent with phosphorylation relieving PLM-mediated inhibition of NKA. Co-immunoprecipitation from rabbit and human cardiac myocytes; immunoblotting for phospho-Ser-68 PLM; Na,K-ATPase activity assay Circulation research Medium 16100047
2005 PLM co-immunoprecipitates with both alpha1 and alpha2 isoforms of Na,K-ATPase in skeletal muscle, and anti-PLM antibody reduces NKA activity, indicating PLM is required for full NKA activity in skeletal muscle. Co-immunoprecipitation from rat skeletal muscle; Na,K-ATPase activity assay with anti-PLM antibody; immunofluorescence localization Journal of applied physiology Medium 15961612
2006 PLM and Na,K-ATPase are in sufficient proximity for FRET when expressed as CFP/YFP fusion proteins in HEK293 cells. PKA activation (Ser-68 phosphorylation) and PKC activation (Ser-63 and Ser-68 phosphorylation) progressively and reversibly decrease NKA–PLM FRET, indicating phosphorylation reduces their physical interaction. PLM–PLM FRET is stronger than NKA–PLM FRET and is enhanced by phosphorylation, consistent with PLM multimerization upon phosphorylation. No FRET was detected between PLM and Na/Ca exchanger despite membrane co-localization. FRET (acceptor photobleach and fluorescence ratio methods) with CFP/YFP fusion proteins in HEK293 cells; PKA/PKC pharmacological activation; phosphorylation state analysis The Journal of biological chemistry High 16943195
2006 PLM mediates the PKC-dependent activation of Na/K-ATPase (NKA) function in cardiac myocytes: PKC activation (PDBu) increases NKA Vmax in wild-type myocytes but has no effect on NKA Vmax or Na+ affinity in PLM-knockout myocytes. PKA (isoproterenol) and PKC effects are additive, acting through different parameters (Na+ affinity and Vmax, respectively). Whole-cell voltage clamp (pump current) and SBFI fluorescence ([Na+]i) measurements in wild-type and PLM-knockout mouse ventricular myocytes; pharmacological PKC and PKA activation Circulation research High 17095720
2007 PKA phosphorylation of PLM at Ser-68 increases the apparent Na+ affinity (decreases K0.5 for Na+) of both NKA-alpha1/beta1 and alpha2/beta1 isozymes without altering maximal transport activity. PKC phosphorylation of PLM increases maximal pump current (turnover number) of alpha2/beta1 but not alpha1/beta1, without affecting K+ affinity of either isozyme. Xenopus oocyte expression of PLM with defined NKA alpha/beta isozymes; two-electrode voltage clamp; PKA and PKC pharmacological activation; PLM phosphorylation-site mutants The Journal of biological chemistry High 17991751
2007 PLM associates with cardiac Na+/Ca2+ exchanger 1 (NCX1) in the sarcolemma and transverse tubules (demonstrated by co-localization and co-immunoprecipitation). PLM inhibits NCX1 independently of its effects on Na,K-ATPase; the cytoplasmic domain of PLM is required for NCX1 regulation. Phosphorylation of PLM at Ser-68 is the active form that inhibits NCX1 (in contrast, unphosphorylated PLM inhibits Na,K-ATPase). Adenovirus-mediated overexpression and siRNA knockdown in adult rat cardiomyocytes; heterologous co-expression in HEK293 cells; co-immunoprecipitation; electrophysiology (NCX1 current); 45Ca2+ uptake; PLM cytoplasmic domain truncation mutants; phosphomimetic and phospho-deficient mutants Annals of the New York Academy of Sciences High 17446450
2009 PLM forms 1:1 stoichiometric complexes with both NKA-alpha1 and NKA-alpha2 (FRET-based). PLM phosphorylation (PKA and PKC) drastically reduces FRET with both isoforms. PLM–PLM FRET indicates oligomers of ≥3 monomers. Isoproterenol (via PKA) increases Na+ affinity of both NKA-alpha1 and alpha2; PKC activation increases Vmax only for NKA-alpha2 but reduces K(1/2) for both. Ouabain abolishes NKA–PLM FRET but only partially reduces co-immunoprecipitation. FRET (progressive acceptor photobleach) in HEK293 cells; cardiac myocytes from WT and NKA-alpha isoform ouabain-sensitivity knock-in mice; whole-cell voltage clamp; SBFI fluorescence; pharmacological PKA/PKC activation The Journal of biological chemistry High 19638348
2010 PLM phosphorylation at either Ser-63 or Ser-68 alone is necessary and sufficient to completely relieve PLM-induced inhibition of NKA Na+ affinity. The double-mutant AA PLM (Ser63Ala/Ser68Ala) cannot be relieved by PKA or PKC activation; single-site mutants S63A or S68A retain responsiveness. HeLa cells stably expressing rat NKA-alpha1; transient expression of WT, S63A, S68A, and AA PLM mutants; SBFI fluorescence for intracellular Na+ concentration; PKA and PKC pharmacological activation American journal of physiology. Cell physiology High 20861470
2012 Surface expression of PLM in Xenopus oocytes requires co-expression with Na,K-ATPase (alpha1/beta1); the Na+/Ca2+ exchanger cannot drive PLM to the cell surface. A phosphorylation-mimicking mutation at Thr-69 or truncation of three C-terminal arginine residues facilitates NKA-dependent surface expression of PLM. Xenopus oocyte expression system; surface biotinylation; co-expression with NKA, NCX; PLM mutants (Thr-69 phosphomimetic, C-terminal truncations) The Journal of biological chemistry Medium 22535957
2013 Two pools of PLM exist in adult rat ventricular myocytes: one pool associated with the sodium pump (phosphorylated at Ser-68 or unphosphorylated) and a separate pool of PLM oligomers not associated with the pump (phosphorylated at Ser-63). PLM multimers co-immunoprecipitate unphosphorylatable PLM from heterozygous transgenic hearts, confirming PLM–PLM multimerization. The non-pump-associated PLM pool has no effect on sodium pump activity upon dephosphorylation. Phosphospecific co-immunoprecipitation from adult rat ventricular myocytes; mass spectrometry; chemical cross-linking; heterozygous transgenic mice expressing WT and unphosphorylatable PLM; sodium pump activity assay The Journal of biological chemistry High 23532852
2013 Nitric oxide (NO) activates Na,K-ATPase via a PKCε–PLM phosphorylation pathway: field stimulation increases endogenous NO, PKCε activation, and PLM phosphorylation (Ser-63 and Ser-68), all of which are abolished by Ca2+ chelation or NOS inhibition. Exogenous NO stimulates NKA in PLM-WT but not PLM-KO or PLM-3SA myocytes, identifying PLM phosphorylation as required for NO-dependent NKA activation. Rat ventricular myocytes; DAF-FM dye (NO), Western blotting (PKCε, phospho-PLM), biochemical NKA assay; perforated-patch clamp in PLM-WT, PLM-KO, and PLM-3SA (unphosphorylatable) myocytes; SBFI fluorescence Journal of molecular and cellular cardiology High 23612119
2013 The transmembrane domain of PLM interacts with TM9 of the NKA alpha-subunit; the cytoplasmic tail of PLM interacts with two small regions (residues 248–252 and 300–304) of the proximal intracellular loop of NCX1. Mutational analysis and heterologous co-expression (cited as prior work summarized in review); co-immunoprecipitation Advances in experimental medicine and biology Low 23224879
2014 Prevention of PLM phosphorylation in PLM-3SA knock-in mice (Ser63/68/69→Ala) increases [Na+]i, reduces forward-mode NCX, exacerbates cardiac hypertrophy and NKA inhibition after aortic constriction compared to WT. In WT mice, aortic constriction causes PLM hypophosphorylation, progressive NKA current decline, and elevated [Na+]i. These data establish that PLM phosphorylation is causally required to maintain NKA activity and limit Na+ overload and adverse remodeling. PLM-3SA knock-in mice; aortic constriction model; echocardiography; pressure-volume catheterization; SBFI fluorescence for [Na+]i; whole-cell patch clamp for NKA current; Western blotting Cardiovascular research High 25103111
2016 Scanning mutagenesis of PLM transmembrane domain identifies residue L30 as critical for PLM–PLM tetramerization (L30A decreases PLM–PLM FRET) and for functional inhibition of NKA. L30A PLM shows increased NKA–PLM FRET and superinhibition of NKA, increasing Ca2+ transient amplitude in cardiomyocytes. These superinhibitory effects are reversible with isoproterenol (PKA activation). Molecular dynamics simulations show L30A distorts the TM helix and destabilizes the tetramer. Scanning mutagenesis of PLM TM domain; FRET in HEK293 cells; Ca2+ transient measurements in isolated cardiomyocytes; molecular dynamics simulations; isoproterenol treatment Biochemistry Medium 27718550
2020 PLM phosphorylation at Ser-63 and Ser-68 limits vascular constriction in response to phenylephrine via Na/K-ATPase (effect blocked by ouabain). PLM-3SA mice (unphosphorylatable PLM) show profoundly enhanced vascular responses to phenylephrine in vitro and in vivo and develop aging-induced hypertension. A human coding variant R70C (SNP rs61753924) prevents PLM phosphorylation at Ser-68 in HEK293 cells and is associated with elevated blood pressure in middle-aged men. PLM-3SA knock-in mice; wire myography of aortic and mesenteric vessels; Doppler flow and telemetry for in vivo BP; HEK293 cell phosphorylation assay; human genomic cohort analyses (UK Biobank, GoDARTS) Circulation High 33334125
2024 Peroxiredoxin 6 (Prdx6) interacts with PLM and depalmitoylates it in a glutathione-dependent manner. Glutathione loading reduces PLM palmitoylation; glutathione depletion increases PLM palmitoylation. Prdx6 silencing abolishes these effects. In vitro, recombinant Prdx6 (but not other Prdx isoforms) removes palmitic acid from palmitoylated recombinant PLM. PLM palmitoylation inhibits Na,K-ATPase activity, and this is reversed by Prdx6-mediated depalmitoylation. The broad-spectrum depalmitoylase inhibitor palmostatin B blocks Prdx6-dependent PLM depalmitoylation in cells and in vitro, suggesting Prdx6 acts as a thioesterase via nucleophilic attack through its reactive thiol. Co-immunoprecipitation of Prdx6 and PLM; acyl-RAC assay for palmitoylation; glutathione loading/depletion in cells; Prdx6 siRNA silencing; in vitro depalmitoylation assay with recombinant proteins; palmostatin B inhibition; Na,K-ATPase activity assay Cell reports High 38236777

Source papers

Stage 0 corpus · 40 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 Mat-8, a novel phospholemman-like protein expressed in human breast tumors, induces a chloride conductance in Xenopus oocytes. The Journal of biological chemistry 138 7836447
2007 Phosphorylation of phospholemman (FXYD1) by protein kinases A and C modulates distinct Na,K-ATPase isozymes. The Journal of biological chemistry 90 17991751
2005 Expression and phosphorylation of the na-pump regulatory subunit phospholemman in heart failure. Circulation research 90 16100047
1994 Protein kinase C and cyclic AMP-dependent protein kinase phosphorylate phospholemman, an insulin and adrenaline-regulated membrane phosphoprotein, at specific sites in the carboxy terminal domain. The Biochemical journal 85 7999001
2003 Phospholemman, a single-span membrane protein, is an accessory protein of Na,K-ATPase in cerebellum and choroid plexus. The Journal of neuroscience : the official journal of the Society for Neuroscience 82 12657675
2009 Isoform specificity of the Na/K-ATPase association and regulation by phospholemman. The Journal of biological chemistry 59 19638348
2006 Phospholemman phosphorylation mediates the protein kinase C-dependent effects on Na+/K+ pump function in cardiac myocytes. Circulation research 53 17095720
2013 Novel regulation of cardiac Na pump via phospholemman. Journal of molecular and cellular cardiology 52 23672825
2006 Phospholemman phosphorylation alters its fluorescence resonance energy transfer with the Na/K-ATPase pump. The Journal of biological chemistry 46 16943195
1997 Characterization of the human and rat phospholemman (PLM) cDNAs and localization of the human PLM gene to chromosome 19q13.1. Genomics 40 9169143
1998 Structural domains in phospholemman: a possible role for the carboxyl terminus in channel inactivation. Circulation research 38 9486665
2014 Cardiac hypertrophy in mice expressing unphosphorylatable phospholemman. Cardiovascular research 37 25103111
2001 Reduction of phospholemman expression decreases osmosensitive taurine efflux in astrocytes. Biochimica et biophysica acta 37 11336802
2000 Phospholemman is a substrate for myotonic dystrophy protein kinase. The Journal of biological chemistry 37 10811636
2009 Phospholemman: its role in normal cardiac physiology and potential as a druggable target in disease. Current opinion in pharmacology 36 19195931
2009 Differential cellular expression of FXYD1 (phospholemman) and FXYD2 (gamma subunit of Na, K-ATPase) in normal human tissues: a study using high density human tissue microarrays. Annals of anatomy = Anatomischer Anzeiger : official organ of the Anatomische Gesellschaft 36 19879113
1999 Modulation of Xenopus oocyte-expressed phospholemman-induced ion currents by co-expression of protein kinases. Biochimica et biophysica acta 35 10556585
2001 Molecular cloning and characterization of a novel phospholemman-like protein from rat hippocampus. Brain research. Molecular brain research 34 11165386
2013 Nitric oxide regulates cardiac intracellular Na⁺ and Ca²⁺ by modulating Na/K ATPase via PKCε and phospholemman-dependent mechanism. Journal of molecular and cellular cardiology 31 23612119
2007 Regulation of cardiac Na+/Ca2+ exchanger by phospholemman. Annals of the New York Academy of Sciences 31 17446450
2005 Expression of phospholemman and its association with Na+-K+-ATPase in skeletal muscle: effects of aging and exercise training. Journal of applied physiology (Bethesda, Md. : 1985) 29 15961612
2013 A separate pool of cardiac phospholemman that does not regulate or associate with the sodium pump: multimers of phospholemman in ventricular muscle. The Journal of biological chemistry 28 23532852
2010 Role of phospholemman phosphorylation sites in mediating kinase-dependent regulation of the Na+-K+-ATPase. American journal of physiology. Cell physiology 28 20861470
2003 Phospholemman expression in extraglomerular mesangium and afferent arteriole of the juxtaglomerular apparatus. American journal of physiology. Renal physiology 25 12657562
2010 Phospholemman: a novel cardiac stress protein. Clinical and translational science 23 20718822
2004 Effects of phospholemman expression on swelling-activated ion currents and volume regulation in embryonic kidney cells. Neurochemical research 23 14992277
2012 Influence of chronic and acute spinal cord injury on skeletal muscle Na+-K+-ATPase and phospholemman expression in humans. American journal of physiology. Endocrinology and metabolism 22 22275761
2006 Multiplicity of expression of FXYD proteins in mammalian cells: dynamic exchange of phospholemman and gamma-subunit in response to stress. American journal of physiology. Cell physiology 22 17050615
2001 Gene structure and expression of phospholemman in mouse. Gene 22 11410367
2013 Coordinated regulation of cardiac Na(+)/Ca (2+) exchanger and Na (+)-K (+)-ATPase by phospholemman (FXYD1). Advances in experimental medicine and biology 21 23224879
2020 Phospholemman Phosphorylation Regulates Vascular Tone, Blood Pressure, and Hypertension in Mice and Humans. Circulation 18 33334125
2024 Glutathione-dependent depalmitoylation of phospholemman by peroxiredoxin 6. Cell reports 11 38236777
2012 Intracellular trafficking of FXYD1 (phospholemman) and FXYD7 proteins in Xenopus oocytes and mammalian cells. The Journal of biological chemistry 11 22535957
2008 Cell volume control in phospholemman (PLM) knockout mice: do cardiac myocytes demonstrate a regulatory volume decrease and is this influenced by deletion of PLM? Experimental physiology 6 19074587
2003 Hypertonic activation of phospholemman in solitary rat hepatocytes in primary culture. FEBS letters 6 12606048
2007 Phospholemman expression is high in the newborn rabbit heart and declines with postnatal maturation. Biochemical and biophysical research communications 5 17303081
2016 L30A Mutation of Phospholemman Mimics Effects of Cardiac Glycosides in Isolated Cardiomyocytes. Biochemistry 4 27718550
2013 Role of phospholemman and the 70 kDa inhibitor protein in regulating Na+/K+ ATPase activity in pulmonary artery smooth muscle cells under U46619 stimulation. FEBS letters 4 24055474
2012 Phospholemman deficiency in postinfarct hearts: enhanced contractility but increased mortality. Clinical and translational science 4 22686200
2022 Discovery and Characterization of the Phospholemman/SIMP/Viroporin Superfamily. Microbial physiology 2 35152214

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