{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n ATP2A2, which encodes the sarco(endo)plasmic reticulum Ca²⁺-ATPase 2 (SERCA2), is a critical regulator of intracellular calcium homeostasis that mediates the reuptake of Ca²⁺ from the cytosol into the sarcoplasmic/endoplasmic reticulum. In cardiac myocytes, SERCA2 activity underlies excitation–contraction coupling and is tightly modulated by phospholamban phosphorylation—processes influenced by kinases such as protein kinase C–α that adjust Ca²⁺ transients and thereby cardiac contractility."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In striated muscle, interactions with structural proteins such as nesprin‐2 help localize SERCA2 to specialized membrane domains, thereby contributing to the maintenance of subcellular architecture."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " Moreover, aberrant alternative splicing of SERCA2 transcripts has been observed in myotonic dystrophy, suggesting that isoform‐specific alterations in ATP2A2 expression can impair Ca²⁺ handling in skeletal muscle."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the heart, diminished expression of ATP2A2 is linked to arrhythmogenic cardiomyopathy—for example, loss of plakophilin-2 reduces SERCA2 levels, which disrupts normal intracellular Ca²⁺ cycling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " Similarly, reduced SERCA2 expression in airway smooth muscle has been associated with abnormal Ca²⁺ reuptake, promoting hyperproliferative and secretory phenotypes in asthma."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Cardiac-specific ablation studies in mice, where SERCA2 levels were reduced to <5%, demonstrate that while minimal activity may temporarily sustain contraction, diastolic function is compromised."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n ATP2A2 expression is also subject to regulation by upstream signaling pathways. Activation of receptors such as MerTK promotes ERK-mediated upregulation of SERCA2, thereby adjusting ER Ca²⁺ stores"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": ", and hypoxia-inducible factor–1α (Hif-1α) has been shown to enhance SERCA2 expression, leading to accelerated Ca²⁺ clearance."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Therapeutically, SERCA2a gene transfer has demonstrated efficacy in pulmonary arterial hypertension by improving vascular remodeling and hemodynamics."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Conversely, inhibition of SERCA2 activity by agents such as curcumin in ovarian cancer cells results in elevated cytosolic Ca²⁺ and triggers apoptosis, underscoring its role in cell survival."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition, protein–protein interactions further regulate SERCA2 function. The ER redox-active protein SEPN1 associates with SERCA2 to enhance its activity under conditions of oxidative stress"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": ", while binding of HAX-1 to SERCA2 modulates its expression and impacts the associated Ca²⁺ stores in cardiomyocytes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": " In platelets from patients with type 2 diabetes, oxidative modifications (tyrosine nitration) of SERCA2 impair Ca²⁺ transport, contributing to dysregulated Ca²⁺ handling and increased thrombotic potential."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these studies underscore that ATP2A2 is pivotal for maintaining Ca²⁺ homeostasis in various tissues. Its precise regulation is essential for normal contractile function, cellular structural integrity, and survival, while its dysregulation contributes to the pathogenesis of diverse cardiovascular, muscular, and metabolic disorders.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Julian C Braz, Kimberly Gregory, Anand Pathak, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PKC-alpha regulates cardiac contractility and propensity toward heart failure."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Med (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nm1000"}], "href": "https://doi.org/10.1038/nm1000"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14966518"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14966518"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Qiuping Zhang, Cassandra D Ragnauth, Jeremy N Skepper, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Nesprin-2 is a multi-isomeric protein that binds lamin and emerin at the nuclear envelope and forms a subcellular network in skeletal muscle."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Sci (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/jcs.01642"}], "href": "https://doi.org/10.1242/jcs.01642"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15671068"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15671068"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Takashi Kimura, Masayuki Nakamori, John D Lueck, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Altered mRNA splicing of the skeletal muscle ryanodine receptor and sarcoplasmic/endoplasmic reticulum Ca2+-ATPase in myotonic dystrophy type 1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddi223"}], "href": "https://doi.org/10.1093/hmg/ddi223"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15972723"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15972723"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Marina Cerrone, Jerome Montnach, Xianming Lin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Plakophilin-2 is required for transcription of genes that control calcium cycling and cardiac rhythm."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41467-017-00127-0"}], "href": "https://doi.org/10.1038/s41467-017-00127-0"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28740174"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28740174"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Katharina Mahn, Stuart J Hirst, Sun Ying, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Diminished sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) expression contributes to airway remodelling in bronchial asthma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0902295106"}], "href": "https://doi.org/10.1073/pnas.0902295106"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19541629"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19541629"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Kristin Brevik Andersson, Jon Arne Kro Birkeland, Alexandra Vanessa Finsen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Moderate heart dysfunction in mice with inducible cardiomyocyte-specific excision of the Serca2 gene."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Mol Cell Cardiol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.yjmcc.2009.03.013"}], "href": "https://doi.org/10.1016/j.yjmcc.2009.03.013"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19328205"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19328205"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Bishuang Cai, Canan Kasikara, Amanda C Doran, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MerTK signaling in macrophages promotes the synthesis of inflammation resolution mediators by suppressing CaMKII activity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Signal (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/scisignal.aar3721"}], "href": "https://doi.org/10.1126/scisignal.aar3721"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30254055"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30254055"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Aaron K Neumann, Jaeseok Yang, Mangat P Biju, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Hypoxia inducible factor 1 alpha regulates T cell receptor signal transduction."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0506070102"}], "href": "https://doi.org/10.1073/pnas.0506070102"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16286658"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16286658"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Lahouaria Hadri, Razmig G Kratlian, Ludovic Benard, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Therapeutic efficacy of AAV1.SERCA2a in monocrotaline-induced pulmonary arterial hypertension."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circulation (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/CIRCULATIONAHA.113.001585"}], "href": "https://doi.org/10.1161/CIRCULATIONAHA.113.001585"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23804254"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23804254"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Jeong-Ah Seo, Boyun Kim, Danny N Dhanasekaran, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Curcumin induces apoptosis by inhibiting sarco/endoplasmic reticulum Ca2+ ATPase activity in ovarian cancer cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Lett (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.canlet.2015.11.021"}], "href": "https://doi.org/10.1016/j.canlet.2015.11.021"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26607901"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26607901"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Marianna Marino, Tatiana Stoilova, Carlotta Giorgi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SEPN1, an endoplasmic reticulum-localized selenoprotein linked to skeletal muscle pathology, counteracts hyperoxidation by means of redox-regulating SERCA2 pump activity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddu602"}], "href": "https://doi.org/10.1093/hmg/ddu602"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25452428"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25452428"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Elizabeth Vafiadaki, Demetrios A Arvanitis, Stamatis N Pagakis, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The anti-apoptotic protein HAX-1 interacts with SERCA2 and regulates its protein levels to promote cell survival."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Biol Cell (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1091/mbc.e08-06-0587"}], "href": "https://doi.org/10.1091/mbc.e08-06-0587"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18971376"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18971376"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Voahanginirina Randriamboavonjy, Frank Pistrosch, Birgit Bölck, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Platelet sarcoplasmic endoplasmic reticulum Ca2+-ATPase and mu-calpain activity are altered in type 2 diabetes mellitus and restored by rosiglitazone."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circulation (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/CIRCULATIONAHA.107.719807"}], "href": "https://doi.org/10.1161/CIRCULATIONAHA.107.719807"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18071073"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18071073"}]}]}]}