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Showing ATP2A1 — SERCA1 is a alias.

ATP2A1

Sarcoplasmic/endoplasmic reticulum calcium ATPase 1 · UniProt O14983

Length
1001 aa
Mass
110.3 kDa
Annotated
2026-06-09
72 papers in source corpus 31 papers cited in narrative 31 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ATP2A1 encodes SERCA1, the fast-twitch skeletal muscle sarcoplasmic/endoplasmic reticulum Ca2+-ATPase that clears cytosolic Ca2+ into the SR lumen to drive muscle relaxation, as established by loss-of-function models in which SERCA1-null mice fail diaphragm contraction and zebrafish atp2a1 mutants show slowed cytosolic Ca2+ decay and sustained muscle co-contraction (PMID:12556521, PMID:15469975). The pump cycles between E1Ca2 and E2 conformations through large rigid-body motions of its N and A domains, with a side-by-side pair of transmembrane Ca2+-binding sites built from M4, M5 and M6 helices (PMID:9789547, PMID:14507684); pharmacological inhibitors such as 4-aminoquinolines and clotrimazole act by stabilizing an E2 state that blocks the E2→E1·Ca2 transition (PMID:21914795). SERCA1 activity is tuned by a network of small transmembrane regulators—sarcolipin and phospholamban lower apparent Ca2+ affinity (sarcolipin additionally raising Vmax), small ankyrin 1 (sAnk1) binds SERCA1 directly and assembles three-way complexes that relieve sarcolipin inhibition, and the muscle-enriched micropeptide MCARE activates the pump by competitively antagonizing the inhibitor myoregulin (PMID:9575189, PMID:17616528, PMID:7651372, PMID:26405035, PMID:28487373, PMID:41372236). Its ER residence is set by an N-terminal retrieval signal in residues 1–211, and its expression is driven by Ebf factors cooperating with MyoD (PMID:12585965, PMID:24786561). Loss-of-function or misfolding mutations in ATP2A1 cause autosomal recessive Brody disease in humans and pseudomyotonia in cattle, with misfolded-but-catalytically-active mutants such as Arg164His cleared by the ubiquitin-proteasome system and rescuable by proteasome inhibition or CFTR correctors (PMID:8841193, PMID:10914677, PMID:18786632, PMID:25288803, PMID:41206505). Aberrant SERCA1 splicing also generates pathology: MBNL1 sequestration in myotonic dystrophy excludes exon 22, and C-terminally truncated S1T variants that retain only partial Ca2+-binding residues form ER-localized leak channels at ER–mitochondria microdomains that deplete ER Ca2+, drive mitochondrial Ca2+ overload, ER stress, and apoptosis (PMID:11402072, PMID:19061639, PMID:17728322).

Mechanistic history

Synthesis pass · year-by-year structured walk · 24 steps
  1. 1996 High

    Established that ATP2A1 is a disease gene, linking SERCA1 loss-of-function to a human muscle relaxation disorder and grounding its physiological role in SR Ca2+ uptake.

    Evidence Genetic linkage and mutation analysis of Brody disease families with SR Ca2+-ATPase activity measurements in patient muscle

    PMID:8841193

    Open questions at the time
    • Did not resolve which mutations cause catalytic versus expression defects
    • No structural mechanism for individual mutations
  2. 1998 High

    Defined the structural basis of Ca2+ binding by mapping the transmembrane helices responsible for the two coordination sites, explaining how the pump captures cytosolic Ca2+.

    Evidence Alanine-scanning mutagenesis and site-directed disulfide cross-linking of M4–M6/M8 helices

    PMID:9789547

    Open questions at the time
    • Coiled-coil model inferred from cross-linking, not full structure
    • Did not address conformational transitions during transport
  3. 1998 High

    Identified sarcolipin as a transmembrane regulator that modulates SERCA1 Ca2+ affinity and Vmax distinctly from phospholamban, opening the micropeptide regulatory network.

    Evidence Co-expression in HEK-293T cells, Ca2+ uptake assays, FLAG tagging and mutagenesis, SR vesicles from stimulated muscle

    PMID:9575189

    Open questions at the time
    • Structural interface with SERCA1 not resolved here
    • Physiological stoichiometry in muscle not quantified
  4. 2000 High

    Demonstrated that disease-mutation phenotype depends on functional impact, distinguishing a causal affinity-disrupting mutation from a benign variant.

    Evidence Site-directed mutagenesis and Ca2+ transport assays of Pro789Leu and Arg819Cys in HEK-293 cells

    PMID:10914677

    Open questions at the time
    • Did not address protein stability or folding of mutants
    • Limited to two variants
  5. 2001 High

    Revealed that truncated SERCA1 splice variants are not merely dead pumps but actively form ER Ca2+ leak channels that trigger apoptosis, establishing a gain-of-toxic-function mechanism.

    Evidence RT-PCR, dimer-detecting Western blot, confocal co-localization, ER-targeted aequorin Ca2+ measurements, apoptosis assays

    PMID:11402072

    Open questions at the time
    • Channel structure of S1T homodimers not defined
    • Physiological relevance in muscle not established here
  6. 2003 High

    Provided the in vivo physiological proof that SERCA1 is essential for fast-twitch muscle relaxation and respiratory function with no compensatory redundancy.

    Evidence SERCA1-null mouse gene targeting, Ca2+ transport Vmax, contractility assays, Ca2+-handling protein profiling

    PMID:12556521

    Open questions at the time
    • Did not test fiber-type-specific rescue
    • Mechanism of perinatal lethality limited to diaphragm phenotype
  7. 2003 High

    Located the ER-retrieval signal that confines SERCA1 to the ER/SR, explaining how the pump achieves its compartment-specific localization.

    Evidence EGFP chimera domain swaps in COS-7 cells with ERGIC53 co-localization

    PMID:12585965

    Open questions at the time
    • Retrieval machinery/receptor not identified
    • Signal residues within 1–211 not narrowed
  8. 2003 Medium

    Modeled the conformational mechanics of the transport cycle, identifying which domains move as rigid bodies during E1-to-E2 transitions.

    Evidence Normal mode analysis of E1Ca2 and E2TG crystal structures with dynamical domain decomposition

    PMID:14507684

    Open questions at the time
    • Computational only, no experimental validation in this study
    • Did not capture regulator-bound states
  9. 2007 High

    Pinpointed the luminal sarcolipin residues that contact SERCA1 and inhibit turnover, giving residue-level resolution to micropeptide regulation.

    Evidence Solid-state NMR, peptide inhibition assays, Ca2+ transport assays with SERCA1a in lipid bilayers

    PMID:17616528

    Open questions at the time
    • IC50 in the micromolar range may not reflect native affinity
    • Full-length interaction interface not mapped
  10. 2007 High

    Explained how SERCA1 splicing is disrupted in myotonic dystrophy by identifying MBNL1 as the direct exon-22 splicing activator that is titrated away by CUG repeats.

    Evidence Exon trapping with mutagenesis of MBNL1 binding motifs and CUG repeat overexpression

    PMID:17728322

    Open questions at the time
    • Functional consequence of exon 22 exclusion on pump activity not measured here
    • Did not address other splice events
  11. 2008 High

    Extended the leak-channel toxic mechanism to ER–mitochondria signaling, showing truncated SERCA1 amplifies mitochondrial Ca2+ overload, ER stress and apoptosis.

    Evidence siRNA knockdown, live-cell Ca2+ imaging, ER-mitochondria contact quantification, PERK-eIF2α-ATF4-CHOP analysis

    PMID:19061639

    Open questions at the time
    • In vivo muscle relevance of the contact-site mechanism not shown
    • Channel conductance properties not measured
  12. 2008 Medium

    Identified a conserved-residue missense mutation causing an animal pseudomyotonia phenotype, providing a naturally occurring model of SERCA1 deficiency.

    Evidence Linkage and mutation analysis with SR ATPase activity in Chianina cattle

    PMID:18786632

    Open questions at the time
    • Mechanism of activity loss not yet defined at this stage
    • Single breed
  13. 2008 Medium

    Resolved that the Arg164His pseudomyotonia defect is loss of pump protein rather than catalytic incompetence, reframing the lesion as a stability problem.

    Evidence Western/Northern blot, ATPase and Ca2+-dependency assays, immunofluorescence in affected cattle muscle

    PMID:19116366

    Open questions at the time
    • Degradation pathway not yet identified
    • Single lab
  14. 2014 High

    Demonstrated that the misfolded Arg164His SERCA1 is destroyed by the proteasome and pharmacologically rescuable, converting a structural lesion into a druggable target.

    Evidence MG132 proteasome inhibition, localization, aequorin Ca2+ assays, ex vivo muscle fibers

    PMID:25288803

    Open questions at the time
    • Did not show clinical-grade rescue strategy
    • Generality across other Brody mutations not tested here
  15. 2014 High

    Established the transcriptional control of SERCA1, showing Ebf factors cooperate with MyoD at the Atp2a1 promoter to drive muscle expression with phenotypic rescue.

    Evidence ChIP of Ebf3 on Atp2a1 promoter, MyoD synergy reporter assays, Ebf3-null mice, transgenic SERCA1 rescue

    PMID:24786561

    Open questions at the time
    • Fiber-type specificity of the regulatory circuit not fully resolved
    • Other upstream signals not mapped
  16. 2015 High

    Added small ankyrin 1 to the regulator network as a direct SERCA1 binder that lowers Ca2+ affinity, expanding the membrane regulatory repertoire beyond SLN/PLN.

    Evidence Co-IP from native SR and transfected cells, AFRET, ATPase assays, TM-domain mutagenesis

    PMID:26405035

    Open questions at the time
    • Cytoplasmic-domain contribution not yet mapped
    • Physiological role in muscle Ca2+ handling not established
  17. 2015 Medium

    Showed SERCA1 splice variants differ functionally, with SERCA1a more active than SERCA1b and SERCA1b enriched in DM1 muscle, linking isoform choice to disease.

    Evidence Overexpression, ATPase and Ca2+ uptake assays, Western blot, immunostaining

    PMID:26170059

    Open questions at the time
    • Structural basis of the activity difference unknown
    • Single lab
  18. 2017 High

    Defined a three-protein regulatory complex in which sAnk1 binds both SLN and SERCA1 and relieves SLN inhibition, revealing combinatorial control of the pump.

    Evidence Co-IP, AFRET, Ca2+-ATPase assays in COS7 cells

    PMID:28487373

    Open questions at the time
    • Native-muscle stoichiometry of the complex not quantified
    • Structural arrangement inferred indirectly
  19. 2018 Medium

    Placed SERCA Ca2+ pumping within ER organelle-contact regulation, where VMP1 activates SERCA and calmodulin/VPS34 maintain inter-organelle contacts.

    Evidence Genetic epistasis in C. elegans, biochemical assays, live imaging of organelle contacts

    PMID:29494262

    Open questions at the time
    • Addresses SERCA broadly, not ATP2A1-specific
    • Direct VMP1–SERCA biochemistry not shown
  20. 2025 Medium

    Refined the sAnk1 mechanism by mapping juxtamembrane and hydrophobic cytoplasmic residues required for binding and inhibition of SERCA1.

    Evidence Mutagenesis, blot-overlay affinity, circular dichroism, ATPase assays, modeling

    PMID:39863105

    Open questions at the time
    • No high-resolution structure of the interface
    • Single lab
  21. 2025 Medium

    Distinguished how PLN versus SLN engage the sAnk1-containing complex, showing sAnk1 does not relieve PLN inhibition, indicating mechanistically distinct regulator modes.

    Evidence Co-IP, BiFC, AFRET, ATPase assays in COS7 cells

    PMID:40998301

    Open questions at the time
    • Native assembly order not directly observed
    • Single lab
  22. 2025 High

    Identified MCARE as a positive regulator that activates SERCA1 by competitively antagonizing the inhibitor myoregulin, with loss causing dystrophy-like fast-twitch pathology.

    Evidence Knockout mice, Ca2+ clearance measurements, interaction and ATPase assays, myoregulin competition assay

    PMID:41372236

    Open questions at the time
    • Structural basis of competition not resolved
    • Interplay with SLN/sAnk1 network not tested
  23. 2025 Medium

    Generalized UPS-mediated degradation of misfolded SERCA1 as a shared pathogenic mechanism and showed CFTR correctors rescue catalytically-active mutants in vivo.

    Evidence CFTR corrector treatment in cellular and bovine pseudomyotonia models, Western blot, Ca2+ homeostasis assays

    PMID:41206505

    Open questions at the time
    • Human Brody disease efficacy not demonstrated
    • Long-term/in vivo durability not addressed
  24. 2025 Medium

    Linked SERCA1 to selective autophagic turnover (SR-phagy) via the ER-phagy receptor FAM134B-S, implicating regulated degradation in statin myotoxicity.

    Evidence Transcriptomics, co-IP/pulldown, autophagy assays, knockdown/overexpression in iPS myocytes and mice (preprint)

    PMID:bio_10.1101_2025.11.26.690680

    Open questions at the time
    • Preprint, not peer-reviewed
    • Direct FAM134B-S binding interface on SERCA1 not mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple micropeptide regulators (SLN, PLN, myoregulin, sAnk1, MCARE) are integrated stoichiometrically and spatially on a single SERCA1 pump in native fast-twitch SR remains unresolved.
  • No native-tissue structure of multi-regulator complexes
  • Quantitative regulator stoichiometry per pump unknown
  • Crosstalk between transcriptional, splicing, and degradative control not unified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 3 GO:0016787 hydrolase activity 3 GO:0140657 ATP-dependent activity 3
Localization
GO:0005783 endoplasmic reticulum 3 GO:0005886 plasma membrane 2
Pathway
R-HSA-1643685 Disease 4 R-HSA-397014 Muscle contraction 3 R-HSA-382551 Transport of small molecules 2
Partners
FAM134BMBNL1MCAREMYOREGULINPLNSANK1SLN
Complex memberships
SERCA1-phospholamban-sAnk1 complexSERCA1-sarcolipin-sAnk1 complex

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 Sarcolipin (SLN) co-localizes with SERCA1 in the ER membrane and regulates its activity: co-expression decreases apparent Ca2+ affinity of SERCA1 but stimulates maximal Ca2+ uptake rates (Vmax). The conserved C-terminal domain of SLN is critical for its function, and SLN and phospholamban (PLN) have different mechanisms of interaction with SERCA1 (additive regulatory effects when both co-expressed). Reduced SLN protein (40% decrease) in chronically stimulated fast-twitch muscle accounts for decreased SERCA1 activity. Co-expression in HEK-293T cells, immunohistochemistry, Ca2+ uptake assays, N- and C-terminal FLAG epitope tagging and mutagenesis, SR vesicle isolation from stimulated muscle The Journal of biological chemistry High 9575189
1996 Mutations in ATP2A1 (encoding SERCA1) cause Brody disease via autosomal recessive inheritance. Three mutations identified: one at the splice donor site of intron 3 and two leading to premature stop codons that truncate SERCA1 and delete essential functional domains, resulting in reduced Ca2+ uptake and Ca2+-ATPase activity in sarcoplasmic reticulum. Genetic linkage, mutation analysis of ATP2A1 gene, SR Ca2+ ATPase activity measurements in patient muscle Nature genetics High 8841193
2000 The missense mutation Pro789Leu in SERCA1 (ATP2A1) causes Brody disease by producing near-complete loss of Ca2+ transport activity due to reduced Ca2+ affinity when expressed in HEK-293 cells. By contrast, Arg819Cys mutation showed near-normal Ca2+ transport activity and was not causal. This demonstrates the importance of functional testing for SERCA1 mutants. Site-directed mutagenesis, expression in HEK-293 cells, Ca2+ transport activity assay Human genetics High 10914677
1998 Alanine-scanning mutagenesis of transmembrane helices M4, M5, M6, and M8 of SERCA1 revealed mutation-sensitive patches in M4, M5, and M6 but not M8. A six-residue motif (E/D)GLPA(T/V) in M4 and M6 and its counterpart in M5 are critical for Ca2+ binding. Site-directed disulfide mapping showed M4 and M6 associate as a right-handed coiled-coil, supporting a 'side-by-side' model for two Ca2+ binding sites. Alanine-scanning mutagenesis, site-directed disulfide mapping of transmembrane helices Acta physiologica Scandinavica. Supplementum High 9789547
2001 Two SERCA1 splice variants (S1Ts) resulting from exon 4 and/or exon 11 splicing encode C-terminally truncated proteins with only one Ca2+-binding residue that cannot pump calcium. These S1T proteins: (1) localize to the ER membrane (co-localizing with SERCA2b); (2) form homodimers; (3) reduce ER Ca2+ concentration and reverse ER Ca2+ elevation caused by full-length SERCA1 or SERCA2b by increasing ER Ca2+ leakage (consistent with cation channel formation by S1T homodimers); (4) significantly induce apoptosis when overexpressed in liver-derived cells. Semi-quantitative RT-PCR, Western blot (including mildly denaturing conditions for dimer detection), confocal microscopy co-localization, ER-targeted aequorin (erAEQ) Ca2+ measurements, transfection, apoptosis assay The Journal of cell biology High 11402072
2000 The HBV X gene promoter cis-activates chimeric HBV X/SERCA1 transcripts with splicing of SERCA1 exon 11, producing C-terminally truncated SERCA1 proteins that form dimers, localize to the ER, cause ER Ca2+ depletion, and induce cell death. These effects are attributable to the SERCA (not viral) moiety of the chimeric proteins. In vivo tumor analysis (HBV DNA integration), in vitro expression analysis, ER localization assay, Ca2+ measurement, cell viability assay Oncogene Medium 10871838
2008 The truncated SERCA1 variant S1T localizes to ER-mitochondria microdomains, causes ER Ca2+ depletion via increased Ca2+ leak, increases the number of ER-mitochondria contact sites, inhibits mitochondria movements, and increases Ca2+ transfer to mitochondria, thereby activating the mitochondrial apoptotic pathway and amplifying ER stress through the PERK-eIF2α-ATF4-CHOP pathway. S1T knockdown prevents ER stress, mitochondrial Ca2+ overload, and apoptosis. siRNA knockdown, live-cell Ca2+ imaging, ER-mitochondria contact site quantification, mitochondria movement tracking, ER stress pathway analysis (Western blot for PERK, eIF2α, ATF4, CHOP), mitochondrial apoptosis assay Molecular cell High 19061639
2003 Targeted disruption of ATP2A1 (SERCA1-null mice) reduces Ca2+ transport activity in diaphragm and skeletal muscle by 80% compared to wild-type. SERCA1-null mice show progressive cyanosis and respiratory failure shortly after birth due to impaired diaphragm muscle contractile function. No compensatory increases in other Ca2+ handling proteins are detected. SERCA1 expression is largely restricted to type II fibers predominating in mouse diaphragm. Gene targeting/knockout, immunohistochemistry, Ca2+ transport Vmax measurement, electrical stimulation contractility assay, mRNA/protein analysis of Ca2+ handling proteins The Journal of biological chemistry High 12556521
2004 In zebrafish, a loss-of-function mutation in atp2a1 (encoding SERCA1) causes the 'accordion' phenotype: bilateral trunk muscle co-contractions due to impaired muscle relaxation. In vivo Ca2+ imaging showed slower cytosolic Ca2+ decay in mutant muscle, confirming defective Ca2+ re-uptake into the SR as the mechanism. Forward genetic screen, positional cloning, in vivo muscle Ca2+ imaging, electrophysiology Development (Cambridge, England) High 15469975
2003 Normal mode analysis of SERCA1 crystal structures (E1Ca2 and E2TG states) revealed that the N and A domains undergo the largest conformational movements during the transport cycle and behave as rigid bodies, while the P domain is highly flexible. Three low-frequency modes are sufficient to describe the E1Ca to E2TG transition, involving closure of the cytoplasmic headpiece and displacement of the L7-8 lumenal loop. Normal mode analysis of crystallographic structures (E1Ca2 and E2TG), DomainFinder dynamical domain analysis Biophysical journal Medium 14507684
2007 MBNL1 binds to 'YGCU(U/G)Y' motifs downstream of SERCA1 exon 22 (specifically the 2nd and 3rd motifs in intron 22) and positively regulates exon 22 inclusion. In DM1, sequestration of MBNL1 into expanded CUG repeat DMPK mRNA causes exclusion of SERCA1 exon 22, producing aberrant SERCA1 transcripts that affect Ca2+ regulation in the sarcoplasmic reticulum. Exon trapping experiments, site-directed mutagenesis of MBNL1 binding motifs, overexpression of CUG repeat expansion Human molecular genetics High 17728322
2007 The conserved C-terminal Tyr29 and Tyr31 residues of sarcolipin directly interact with SERCA1a at the luminal face. The peptide NAc-RSYQY representing this region binds SERCA1 and reduces Vmax for Ca2+ transport and inhibits ATP hydrolysis (IC50 ~200 µM). Native aromatic residues are essential for optimal inhibitory activity. Solid-state NMR (local protein dynamics), functional Ca2+ transport assays, peptide inhibition assays with SERCA1a in lipid bilayers The Journal of biological chemistry High 17616528
2003 The N-terminal segment of SERCA1 (residues 1–211, containing transmembrane helices M1 and M2) contains an ER-retrieval signal. Chimeras containing the SERCA1 N-terminus localized to the ER, while those with the PMCA3 N-terminus escaped the ER. SERCA1 is maintained in the ER by a retrieval process (co-localization with ERGIC53). EGFP-tagged chimera expression in COS-7 cells, subcellular localization by confocal microscopy, co-localization with ER/Golgi intermediate compartment marker ERGIC53 The Biochemical journal High 12585965
1995 Phospholamban (PLN), when stably transfected into C2C12 fast-twitch skeletal muscle cells expressing endogenous SERCA1, inhibits SERCA1 activity by decreasing its Ca2+ affinity (apparent Km shifted from 0.27 to 0.41 µM) at low Ca2+ concentrations in the native membrane environment. Stable transfection of PLN into C2C12 myotubes, 45Ca2+-uptake assay over range of Ca2+ concentrations, Western blot, microsomal fractionation Molecular and cellular biochemistry Medium 7651372
2008 A missense mutation in ATP2A1 exon 6 (c.491G>A; p.Arg164His) causes congenital pseudomyotonia in Chianina cattle by reducing SERCA1 activity by ~70%. Arg164 is a functionally important and strongly conserved residue of SERCA1. Linkage analysis, mutation analysis, SERCA1 ATPase activity measurement in SR membranes from affected cattle Genomics Medium 18786632
2008 The Arg164His SERCA1 mutant (bovine pseudomyotonia) shows selective reduction of SERCA1 protein in SR membranes despite normal mRNA levels, without significant change in Ca2+-dependency of residual ATPase activity and without compensatory upregulation of SERCA2. The protein reduction (not catalytic deficiency) accounts for the reduced activity. Western blot, Northern blot, SERCA1 ATPase activity assay, Ca2+-dependency measurement, immunofluorescence The American journal of pathology Medium 19116366
2014 The Arg164His SERCA1 mutant (Chianina pseudomyotonia) is degraded by the ubiquitin-proteasome system (UPS). Treatment with proteasome inhibitor MG132 rescues expression level and membrane localization of the mutant in a heterologous cellular model. The rescued mutant retains normal Ca2+ homeostasis maintenance ability. Ex vivo skeletal muscle fibers from affected animals confirmed these findings, indicating the mutation causes misfolding rather than catalytic inactivation. Proteasome inhibitor treatment (MG132), Western blot, immunofluorescence localization, Ca2+-sensitive aequorin probe in co-transfected cells, ex vivo adult muscle fiber analysis The Journal of biological chemistry High 25288803
2014 Transcription factors Ebf3 and Ebf1 cooperate with MyoD to directly regulate Atp2a1 (SERCA1) expression in skeletal muscle. Ebf3 binds directly to the Atp2a1 promoter and synergizes with MyoD for Atp2a1 induction. In Ebf3-null mice, SERCA1 is downregulated in the diaphragm, causing impaired Ca2+ efflux-related muscle function; transgenic SERCA1 expression rescues this phenotype. ChIP (Ebf3 binding to Atp2a1 promoter), reporter assay (synergy with MyoD), knockout mouse analysis, transgenic rescue, Ca2+ efflux measurements Nature communications High 24786561
2015 Small ankyrin 1 (sAnk1) interacts specifically with SERCA1 via its transmembrane domain and its cytoplasmic domain. This interaction is demonstrated in native SR vesicles from rabbit skeletal muscle and in transfected COS7 cells. sAnk1 co-expression reduces the apparent Ca2+ affinity of SERCA1 but the effect is smaller than sarcolipin. Replacement of all TM amino acids with leucines reduces binding ~2-fold and abolishes the effect on SERCA1 activity. Co-immunoprecipitation from native SR vesicles and transfected cells, anisotropy-based FRET (AFRET), ATPase activity assay, TM domain mutagenesis The Journal of biological chemistry High 26405035
2017 sAnk1 and SLN interact directly and form a three-protein complex with SERCA1 in the SR membrane. SLN promotes the interaction between sAnk1 and SERCA1. When sAnk1 and SLN are co-expressed with SERCA1, sAnk1 ablates SLN's inhibitory effect on SERCA1 activity. The sAnk1-SLN interaction does not require endogenous SERCA2. Co-immunoprecipitation, anisotropy-based FRET (AFRET), Ca2+-ATPase activity assay, co-transfection in COS7 cells The Journal of biological chemistry High 28487373
2015 SERCA1a has approximately double the ATPase and Ca2+ uptake activity of SERCA1b when overexpressed in cells, despite similar affinities for ATP and Ca2+. SERCA1b is more sensitive to the inner microsomal environment. SERCA1b protein is highly expressed in DM1 muscle tissue, predominantly in fast-twitch fibers. Overexpression in cells, ATPase activity assay, Ca2+ uptake assay, Western blot, immunostaining Biochimica et biophysica acta Medium 26170059
2011 4-aminoquinoline derivatives (NF1442 and NF1058) and clotrimazole inhibit SERCA1 by stabilizing an E2 state that interferes with Ca2+ binding and the E2→E1·Ca2 transition required for phosphoenzyme formation by ATP, but this E2 state retains the ability to form E2-P by reacting with Pi. This is mechanistically distinct from thapsigargin, which also inhibits Pi-dependent phosphorylation. Steady-state ATPase activity assay, single-cycle charge transfer measurement, sequential reaction kinetic characterization of phosphoenzyme formation The Journal of biological chemistry High 21914795
2003 SERCA1 (RyR1/SERCA1 cross-talk): In heavy SR vesicles, SERCA1 ATPase catalytic activity is well coordinated to RyR1 activation/inactivation states. Ryanodine-induced Ca2+ channel leak activates SERCA1 in the absence of measurable bulk Ca2+ increase, suggesting SERCA1 pumps sense Ca2+ ions exiting RyR1 cytoplasmic openings. Conversely, RyR1 activation is dependent on SERCA1 activity; at threshold luminal Ca2+ load, RyR1-induced Ca2+ release produces transient reversal of SERCA1 catalytic activity. Synchronous fluorescence determination of extravesicular Ca2+ transients and catalytic activity in heavy SR membrane vesicles, ryanodine receptor pharmacology Canadian journal of physiology and pharmacology Medium 12733821
2000 The rat SERCA1 5' flanking region contains weight-bearing responsive elements. Specific CACC box at -1262 and a nearby E-box at -1248 are necessary and sufficient for transcriptional activation by muscle unloading. Both elements together are required to activate transcription; trimerized CACC sites alone are insufficient. In vivo somatic gene transfer into rat soleus muscle, deletion analysis of SERCA1 promoter/5' flank, mutagenesis of cis-elements, luciferase reporter assay The Journal of biological chemistry Medium 10811813
2018 The ER-localized autophagy protein EPG-3/VMP1 regulates ER contacts with other organelles (phagophores, lipid droplets, mitochondria, endolysosomes) by activating SERCA (ATP2A/SERCA) calcium channel activity. Downstream, calmodulin (CALM) acts as a calcium effector controlling PIK3C3/VPS34 PI3-kinase activity to maintain ER contacts. Genetic epistasis in C. elegans, biochemical assays, live imaging of organelle contacts Autophagy Medium 29494262
2012 PKC signaling regulates alternative splicing of SERCA1. PMA treatment regulates SERCA1 exon splicing in HEK293 cells; prolonged PMA (48h) normalizes SERCA1 splicing while short treatment (1.5h) promotes aberrant splicing. Both effects are abolished by PKC inhibitor Ro 31-8220. RNAi knockdown of PKCβII and PKCθ mimics prolonged PMA treatment (normalized splicing). PMA treatment, PKC inhibitor treatment, RNAi knockdown of PKC isoforms, RT-PCR splicing assay Biochemical and biophysical research communications Medium 22609207
2025 A novel small transmembrane protein MCARE (muscle-enriched Ca2+ regulator), predominantly expressed in fast-twitch muscles, enhances SERCA1 function by competitively inhibiting myoregulin (a muscle-specific micropeptide that suppresses SERCA1 activity). MCARE-mediated SERCA1 activation facilitates Ca2+ clearance from the cytoplasm and accelerates muscle relaxation. Mcare-deficient mice show muscular dystrophy-like symptoms (progressive muscle wasting, reduced strength, increased susceptibility to exercise-induced damage, rippling muscle contractions) in fast-twitch muscles. Knockout mouse model, Ca2+ clearance measurements, protein interaction studies, ATPase activity assays, competition assay with myoregulin Nature communications High 41372236
2025 The juxtamembrane region of sAnk1 cytoplasmic domain (residues K38, H39, H41) and hydrophobic residues R64-K73 mediate binding to SERCA1. The cytoplasmic domain alone (sAnk1(29-155)) does not inhibit SERCA1 Ca2+-ATPase activity, but the WT juxtamembrane sequence is required for the inhibitory activity of full-length sAnk1. Binding affinity of sAnk1(29-155) for SERCA1 is 444 nM by blot overlay. Site-directed mutagenesis, blot overlay binding affinity measurement, circular dichroism, ATPase activity assay, structural modeling The Journal of biological chemistry Medium 39863105
2025 sAnk1 associates with phospholamban (PLN) and forms a three-way complex with PLN and SERCA1, as shown by co-IP and BiFC in COS7 cells and confirmed by AFRET. Unlike its effect on SLN inhibition, sAnk1 does not ablate PLN's inhibition of SERCA1 activity. Modeling suggests PLN binds SERCA1 first, then sAnk1 binds PLN; the interactions of PLN, SLN, and sAnk1 with SERCA1 are mechanistically distinct. Co-transfection, co-immunoprecipitation, bimolecular fluorescence complementation (BiFC), anisotropy-based FRET (AFRET), ATPase activity assay Biochemistry Medium 40998301
2025 FAM134B short isoform (FAM134B-S), an ER-phagy receptor induced by statins via the mevalonate pathway and SREBPs, interacts with SERCA1 and promotes its autophagic degradation (SR-phagy). This degradation mechanism contributes to statin-associated muscle symptoms and myotoxicity. FAM134B plays a role in maintaining skeletal muscle integrity under both steady-state and statin-treated conditions in human iPS-derived myocytes and mice. Transcriptome analysis, protein-protein interaction studies (co-IP/pulldown), autophagy assays, knockdown/overexpression in iPS-derived myocytes and mice, pathway analysis (mevalonate pathway inhibition) bioRxivpreprint Medium bio_10.1101_2025.11.26.690680
2025 CFTR correctors, particularly C17, rescue SERCA1 missense mutants (Brody myopathy/bovine pseudomyotonia) both in vitro and in vivo by counteracting premature proteasomal degradation of misfolded-but-catalytically-active SERCA1 mutant proteins. This identifies UPS-mediated degradation of misfolded SERCA1 as the shared pathogenetic mechanism with cystic fibrosis. CFTR corrector treatment in cellular and animal models, Western blot for SERCA1 rescue, Ca2+ homeostasis assays, in vivo bovine PMT model Human molecular genetics Medium 41206505

Source papers

Stage 0 corpus · 72 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Role of SERCA1 truncated isoform in the proapoptotic calcium transfer from ER to mitochondria during ER stress. Molecular cell 200 19061639
1998 Sarcolipin regulates the activity of SERCA1, the fast-twitch skeletal muscle sarcoplasmic reticulum Ca2+-ATPase. The Journal of biological chemistry 197 9575189
1996 Mutations in the gene-encoding SERCA1, the fast-twitch skeletal muscle sarcoplasmic reticulum Ca2+ ATPase, are associated with Brody disease. Nature genetics 179 8841193
1997 Characterization of the gene encoding human sarcolipin (SLN), a proteolipid associated with SERCA1: absence of structural mutations in five patients with Brody disease. Genomics 133 9367679
2007 Molecular mechanisms responsible for aberrant splicing of SERCA1 in myotonic dystrophy type 1. Human molecular genetics 81 17728322
2001 SERCA1 truncated proteins unable to pump calcium reduce the endoplasmic reticulum calcium concentration and induce apoptosis. The Journal of cell biology 66 11402072
2003 Targeted disruption of the ATP2A1 gene encoding the sarco(endo)plasmic reticulum Ca2+ ATPase isoform 1 (SERCA1) impairs diaphragm function and is lethal in neonatal mice. The Journal of biological chemistry 64 12556521
2000 The mutation of Pro789 to Leu reduces the activity of the fast-twitch skeletal muscle sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA1) and is associated with Brody disease. Human genetics 63 10914677
1995 Characterization of cDNA and genomic DNA encoding SERCA1, the Ca(2+)-ATPase of human fast-twitch skeletal muscle sarcoplasmic reticulum, and its elimination as a candidate gene for Brody disease. Genomics 61 8825625
2004 accordion, a zebrafish behavioral mutant, has a muscle relaxation defect due to a mutation in the ATPase Ca2+ pump SERCA1. Development (Cambridge, England) 60 15469975
2000 Hepatitis B virus-related insertional mutagenesis implicates SERCA1 gene in the control of apoptosis. Oncogene 54 10871838
2015 SERCA1 overexpression minimizes skeletal muscle damage in dystrophic mouse models. American journal of physiology. Cell physiology 50 25652448
2003 Transconformations of the SERCA1 Ca-ATPase: a normal mode study. Biophysical journal 49 14507684
1998 Cell-specific promoter in adenovirus vector for transgenic expression of SERCA1 ATPase in cardiac myocytes. The American journal of physiology 49 9530095
2002 Dual gene therapy with SERCA1 and Kir2.1 abbreviates excitation without suppressing contractility. The Journal of clinical investigation 47 11827999
2014 Ebf factors and MyoD cooperate to regulate muscle relaxation via Atp2a1. Nature communications 45 24786561
1999 Comparison of SERCA1 and SERCA2a expressed in COS-1 cells and cardiac myocytes. The American journal of physiology 44 10600859
2008 Identification of a missense mutation in the bovine ATP2A1 gene in congenital pseudomyotonia of Chianina cattle: an animal model of human Brody disease. Genomics 38 18786632
2008 A defective SERCA1 protein is responsible for congenital pseudomyotonia in Chianina cattle. The American journal of pathology 31 19116366
2010 Brody disease: insights into biochemical features of SERCA1 and identification of a novel mutation. Journal of neuropathology and experimental neurology 24 20142766
2015 Functional analysis of SERCA1b, a highly expressed SERCA1 variant in myotonic dystrophy type 1 muscle. Biochimica et biophysica acta 22 26170059
2003 Sarco(endo)plasmic reticulum Ca2+ ATPases (SERCA1 and -2) in human extraocular muscles. Investigative ophthalmology & visual science 22 14638697
2017 Interactions between small ankyrin 1 and sarcolipin coordinately regulate activity of the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA1). The Journal of biological chemistry 20 28487373
2015 Identification of Small Ankyrin 1 as a Novel Sarco(endo)plasmic Reticulum Ca2+-ATPase 1 (SERCA1) Regulatory Protein in Skeletal Muscle. The Journal of biological chemistry 20 26405035
2008 Limited functional and metabolic improvements in hypertrophic and healthy rat heart overexpressing the skeletal muscle isoform of SERCA1 by adenoviral gene transfer in vivo. American journal of physiology. Heart and circulatory physiology 20 18952713
2006 SERCA1 and calsequestrin storage myopathy: a new surplus protein myopathy. Brain : a journal of neurology 20 16714317
2014 Inhibition of ubiquitin proteasome system rescues the defective sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA1) protein causing Chianina cattle pseudomyotonia. The Journal of biological chemistry 19 25288803
2007 Solid-state NMR and functional measurements indicate that the conserved tyrosine residues of sarcolipin are involved directly in the inhibition of SERCA1. The Journal of biological chemistry 19 17616528
1997 Fast- and slow-twitch isoforms (SERCA1 and SERCA2a) of sarcoplasmic reticulum Ca-ATPase are expressed simultaneously in chronically stimulated muscle fibers. Pflugers Archiv : European journal of physiology 19 9049168
2009 SERCA1 expression enhances the metabolic efficiency of improved contractility in post-ischemic heart. Journal of molecular and cellular cardiology 18 19744494
2010 Evidence for a new allele at the SERCA1 locus affecting pork meat quality in part through the imbalance of Ca2+ homeostasis. Molecular biology reports 15 19821152
1999 Normalization of muscle plasmid uptake by Southern blot: application to SERCA1 promoter analysis. The American journal of physiology 15 10600779
2018 The ER-localized autophagy protein EPG-3/VMP1 regulates ER contacts with other organelles by modulating ATP2A/SERCA activity. Autophagy 14 29494262
2010 Analysis of a zebrafish behavioral mutant reveals a dominant mutation in atp2a1/SERCA1. Genesis (New York, N.Y. : 2000) 14 20533403
2010 Pseudomyotonia, a muscle function disorder associated with an inherited ATP2A1 (SERCA1) defect in a Dutch Improved Red and White cross-breed calf. Neuromuscular disorders : NMD 14 20547455
2006 Exclusion of linkage of the RYR1, CACNA1S, and ATP2A1 genes to recurrent exertional rhabdomyolysis in Thoroughbreds. American journal of veterinary research 14 16881852
2003 Sarco/endoplasmic-reticulum calcium ATPase SERCA1 is maintained in the endoplasmic reticulum by a retrieval signal located between residues 1 and 211. The Biochemical journal 14 12585965
2000 Identification of weight-bearing-responsive elements in the skeletal muscle sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA1) gene. The Journal of biological chemistry 14 10811813
1998 Structure-function relationships in the Ca(2+)-binding and translocation domain of SERCA1: physiological correlates in Brody disease. Acta physiologica Scandinavica. Supplementum 14 9789547
2012 Pseudomyotonia in Romagnola cattle caused by novel ATP2A1 mutations. BMC veterinary research 13 23046865
1995 Expression of phospholamban in C2C12 cells and regulation of endogenous SERCA1 activity. Molecular and cellular biochemistry 13 7651372
2020 The Dimeric Form of 1,3-Diaminoisoquinoline Derivative Rescued the Mis-splicing of Atp2a1 and Clcn1 Genes in Myotonic Dystrophy Type 1 Mouse Model. Chemistry (Weinheim an der Bergstrasse, Germany) 12 32449537
2014 Inhibition of the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA1) by rutin derivatives. Journal of muscle research and cell motility 12 25467059
2019 Identification of a pathogenic mutation in ATP2A1 via in silico analysis of exome data for cryptic aberrant splice sites. Molecular genetics & genomic medicine 11 30688039
2016 Slowed relaxation of diaphragm in septic rats is associated with reduced expression of sarco-endoplasmic reticulum CA2+ -ATPase genes SERCA1 and SERCA2. Muscle & nerve 11 27104787
2012 Regulation of the alternative splicing of sarcoplasmic reticulum Ca²⁺-ATPase1 (SERCA1) by phorbol 12-myristate 13-acetate (PMA) via a PKC pathway. Biochemical and biophysical research communications 10 22609207
2011 The Ca2+-ATPase (SERCA1) is inhibited by 4-aminoquinoline derivatives through interference with catalytic activation by Ca2+, whereas the ATPase E2 state remains functional. The Journal of biological chemistry 10 21914795
2010 Tissue-specific expression of Sarcoplasmic/Endoplasmic Reticulum Calcium ATPases (ATP2A/SERCA) 1, 2, 3 during Xenopus laevis development. Gene expression patterns : GEP 10 21074636
2014 Rutin stimulates sarcoplasmic reticulum Ca(2+)-ATPase activity (SERCA1) and protects SERCA1 from peroxynitrite mediated injury. Molecular and cellular biochemistry 9 25547066
2004 Method-related effects of adenovirus-mediated LacZ and SERCA1 gene transfer on contractile behavior of cultured failing human cardiomyocytes. Journal of pharmacological and toxicological methods 8 15767202
1997 Correlations between MyoD, myogenin, SERCA1, SERCA2 and phospholamban transcripts during transformation of type-II to type-I skeletal muscle fibers. Pflugers Archiv : European journal of physiology 8 9136677
2024 SERCA1 Overexpression in Skeletal Muscle Attenuates Muscle Atrophy and Improves Motor Function in a Mouse Model of ALS. Journal of neuromuscular diseases 7 38217607
2004 Adenoviral SERCA1 overexpression triggers an apoptotic response in cultured neonatal but not in adult rat cardiomyocytes. Molecular and cellular biochemistry 7 15663193
2022 Differential Analysis of Gly211Val and Gly286Val Mutations Affecting Sarco(endo)plasmic Reticulum Ca2+-ATPase (SERCA1) in Congenital Pseudomyotonia Romagnola Cattle. International journal of molecular sciences 6 36293223
2017 SERCA1 attenuates diaphragm relaxation and uptake rate of SERCA in rats with acute sepsis. Molecular medicine reports 6 28765908
2003 RyR1/SERCA1 cross-talk regulation of calcium transport in heavy sarcoplasmic reticulum vesicles. Canadian journal of physiology and pharmacology 5 12733821
2023 Curcumin Administration Improves Force of mdx Dystrophic Diaphragm by Acting on Fiber-Type Composition, Myosin Nitrotyrosination and SERCA1 Protein Levels. Antioxidants (Basel, Switzerland) 4 37371910
2023 Sarcolipin (sln) and Sarcoplasmic Reticulum calcium ATPase pump (serca1) expression increase in Japanese medaka (Oryzias latipes) skeletal muscle tissue following cold challenge. Comparative biochemistry and physiology. Part A, Molecular & integrative physiology 4 37844835
2018 Investigating PIK3R3 and ATp2A1 Genes Expressions in Ventilator-Associated Pneumonia Patients Admitted to the Intensive Care Unit of Masih Daneshvari Hospital in 2016. Reports of biochemistry & molecular biology 4 29765993
2015 Fast-twitch skeletal muscle fiber adaptation to SERCA1 deficiency in a Dutch Improved Red and White calf pseudomyotonia case. Neuromuscular disorders : NMD 4 26482047
2025 The juxtamembrane sequence of small ankyrin 1 mediates the binding of its cytoplasmic domain to SERCA1 and is required for inhibitory activity. The Journal of biological chemistry 3 39863105
2010 Immunohistochemical evidence for expression of fast-twitch type sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA1) in German shepherd dogs with dilated cardiomyopathy myocardium. Journal of veterinary cardiology : the official journal of the European Society of Veterinary Cardiology 3 20188644
2024 Relative sarcolipin (SLN) and sarcoplasmic reticulum Ca2+ ATPase (SERCA1) transcripts levels in closely related endothermic and ectothermic scombrid fishes: Implications for molecular basis of futile calcium cycle non-shivering thermogenesis (NST). Comparative biochemistry and physiology. Part A, Molecular & integrative physiology 2 38782254
2013 Measurement of Ca²⁺-ATPase activity (in PMCA and SERCA1). Methods in molecular biology (Clifton, N.J.) 2 23007597
2025 Discovery of SERCA1-specific small molecule inhibitors based on survival mechanisms in metastatic hepatocellular carcinoma cells that depend on CaMK2α-mediated SERCA1 expression. Biochemical pharmacology 1 41086920
2025 Structural Conservation and Transcriptional Plasticity of atp2a1 in Acrossocheilus fasciatus Under Temperature and Flow Acclimation. Genes 1 41300837
2016 [Lowered sarcoendoplasmic reticulum calcium uptake and diaphragmatic SERCA1 expression contribute to diaphragmatic contractile and relaxation dysfunction in septic rats]. Nan fang yi ke da xue xue bao = Journal of Southern Medical University 1 28446393
2014 Kinetic characterization of Ca²⁺-ATPase (SERCA1) inhibition by tri-n-butyltin(IV) chloride. A docking conformation proposal. Journal of biomolecular structure & dynamics 1 24999014
2005 Measurement of Ca²+-ATPase activity (in PMCA and SERCA1). Methods in molecular biology (Clifton, N.J.) 1 21341110
2025 Small Ankyrin 1 Interacts with Phospholamban and Forms a Three-Way Complex with SERCA1. Biochemistry 0 40998301
2025 CFTR corrector C17 rescues defective SERCA1 in bovine pseudomyotonia: a potential therapy for Brody myopathy. Human molecular genetics 0 41206505
2025 MCARE enhances SERCA1 activity in fast-twitch muscle to maintain calcium handling and muscle integrity. Nature communications 0 41372236

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