{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nAlthough the query requested a summary of PLPP6 function, none of the provided abstracts mention PLPP6. Instead, the collective literature focuses on S100A1—a small, EF‐hand Ca²⁺‐binding protein that plays multifaceted roles in striated muscle and vascular biology. In the heart, diminished S100A1 levels are a hallmark of cardiomyopathy and heart failure, while its overexpression improves contractility by enhancing Ca²⁺ cycling and sarcoplasmic reticulum function. S100A1 also associates with mitochondrial F₁‐ATPase to boost ATP production, underscoring its role in linking Ca²⁺ signaling with energy metabolism."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn skeletal muscle, S100A1 enhances excitation–contraction coupling by promoting Ca²⁺ release from the sarcoplasmic reticulum through specific interactions with the ryanodine receptor. Its Ca²⁺‐dependent binding, which competes with calmodulin at overlapping sites, finely tunes SR Ca²⁺ flux to ensure efficient contractile performance in both fast‐ and slow‐twitch fibers. This optimization of intracellular Ca²⁺ signals is critical for maintaining muscle force production without impairing Ca²⁺ reuptake during repeated stimulation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nS100A1 also exerts important functions in the vasculature by modulating endothelial nitric oxide synthase activity and nitric oxide production, thereby contributing to endothelium‐dependent vasorelaxation and blood pressure regulation. In conditions of hypoxia or tissue injury, S100A1 is not only downregulated in endothelial cells—leading to impaired NO release and vascular dysfunction—but can also be released from necrotic cardiomyocytes to act as an alarmin that influences inflammatory and reparative responses. Moreover, emerging evidence indicates roles for S100A1 in neural and epithelial differentiation as well as in the modulation of intracellular signaling cascades (such as via protein kinase A activation), highlighting its broad regulatory impact across tissues."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn summary, while the original query pertained to the function of PLPP6, the provided abstracts do not address PLPP6 at all. Rather, they collectively delineate the diverse roles of S100A1 in orchestrating Ca²⁺-dependent signaling processes that underpin cardiac contractility, skeletal muscle excitation–contraction coupling, endothelial-mediated vascular regulation, and additional cellular functions. This body of work underscores the therapeutic potential of targeting S100A1 in a variety of cardiovascular and neuromuscular disorders."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "18", "end_ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Patrick Most, Andrew Remppis, Sven T Pleger, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Transgenic overexpression of the Ca2+-binding protein S100A1 in the heart leads to increased in vivo myocardial contractile performance."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M301788200"}], "href": "https://doi.org/10.1074/jbc.M301788200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12777394"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12777394"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Patrick Most, Hanna Seifert, Erhe Gao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cardiac S100A1 protein levels determine contractile performance and propensity toward heart failure after myocardial infarction."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circulation (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/CIRCULATIONAHA.106.622415"}], "href": "https://doi.org/10.1161/CIRCULATIONAHA.106.622415"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16952982"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16952982"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Melanie Boerries, Patrick Most, Jonathan R Gledhill, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Ca2+ -dependent interaction of S100A1 with F1-ATPase leads to an increased ATP content in cardiomyocytes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.02045-06"}], "href": "https://doi.org/10.1128/MCB.02045-06"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17438143"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17438143"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Jean-Francois Desjardins, Ali Pourdjabbar, Adrian Quan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Lack of S100A1 in mice confers a gender-dependent hypertensive phenotype and increased mortality after myocardial infarction."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Physiol Heart Circ Physiol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1152/ajpheart.00088.2008"}], "href": "https://doi.org/10.1152/ajpheart.00088.2008"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19286962"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19286962"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Konstantin Gusev, Gabriele E Ackermann, Claus W Heizmann, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Ca2+ signaling in mouse cardiomyocytes with ablated S100A1 protein."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gen Physiol Biophys (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4149/gpb_2009_04_371"}], "href": "https://doi.org/10.4149/gpb_2009_04_371"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20097960"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20097960"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Patrick Most, Andrew Remppis, Cornelia Weber, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The C terminus (amino acids 75-94) and the linker region (amino acids 42-54) of the Ca2+-binding protein S100A1 differentially enhance sarcoplasmic Ca2+ release in murine skinned skeletal muscle fibers."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M303338200"}], "href": "https://doi.org/10.1074/jbc.M303338200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12721284"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12721284"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Nathan T Wright, Benjamin L Prosser, Kristen M Varney, et al. "}, {"type": "b", "children": [{"type": "t", "text": "S100A1 and calmodulin compete for the same binding site on ryanodine receptor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M804432200"}], "href": "https://doi.org/10.1074/jbc.M804432200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18650434"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18650434"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Benjamin L Prosser, Nathan T Wright, Erick O Hernãndez-Ochoa, et al. "}, {"type": "b", "children": [{"type": "t", "text": "S100A1 binds to the calmodulin-binding site of ryanodine receptor and modulates skeletal muscle excitation-contraction coupling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M709231200"}], "href": "https://doi.org/10.1074/jbc.M709231200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18089560"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18089560"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Naohiro Yamaguchi, Benjamin L Prosser, Farshid Ghassemi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Modulation of sarcoplasmic reticulum Ca2+ release in skeletal muscle expressing ryanodine receptor impaired in regulation by calmodulin and S100A1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Physiol Cell Physiol (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1152/ajpcell.00370.2010"}], "href": "https://doi.org/10.1152/ajpcell.00370.2010"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21289290"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21289290"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Benjamin L Prosser, Erick O Hernández-Ochoa, Richard M Lovering, et al. "}, {"type": "b", "children": [{"type": "t", "text": "S100A1 promotes action potential-initiated calcium release flux and force production in skeletal muscle."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Physiol Cell Physiol (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1152/ajpcell.00180.2010"}], "href": "https://doi.org/10.1152/ajpcell.00180.2010"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20686070"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20686070"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Sven T Pleger, David M Harris, Changguang Shan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Endothelial S100A1 modulates vascular function via nitric oxide."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circ Res (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/CIRCRESAHA.108.172031"}], "href": "https://doi.org/10.1161/CIRCRESAHA.108.172031"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18292599"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18292599"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Patrick Most, Carolin Lerchenmüller, Giuseppe Rengo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "S100A1 deficiency impairs postischemic angiogenesis via compromised proangiogenic endothelial cell function and nitric oxide synthase regulation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circ Res (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/CIRCRESAHA.112.275156"}], "href": "https://doi.org/10.1161/CIRCRESAHA.112.275156"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23048072"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23048072"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Anagha Sen, Shumei Ren, Carolin Lerchenmüller, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MicroRNA-138 regulates hypoxia-induced endothelial cell dysfunction by targeting S100A1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0078684"}], "href": "https://doi.org/10.1371/journal.pone.0078684"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24244340"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24244340"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Michael Reppel, Philipp Sasse, Roland Piekorz, et al. "}, {"type": "b", "children": [{"type": "t", "text": "S100A1 enhances the L-type Ca2+ current in embryonic mouse and neonatal rat ventricular cardiomyocytes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M504750200"}], "href": "https://doi.org/10.1074/jbc.M504750200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16129693"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16129693"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Zephan Melville, Erick O Hernández-Ochoa, Stephen J P Pratt, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The Activation of Protein Kinase A by the Calcium-Binding Protein S100A1 Is Independent of Cyclic AMP."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochemistry (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1021/acs.biochem.7b00117"}], "href": "https://doi.org/10.1021/acs.biochem.7b00117"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28409622"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28409622"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Fairouz Qasrawi, Max Meuser, Finja Lehnhoff, et al. "}, {"type": "b", "children": [{"type": "t", "text": "S100A1 expression characterizes terminally differentiated superficial cells in the urothelium of the murine bladder and ureter."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Histochem Cell Biol (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00418-022-02120-1"}], "href": "https://doi.org/10.1007/s00418-022-02120-1"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35648290"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35648290"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Andreas Seitz, Martin Busch, Jasmin Kroemer, et al. "}, {"type": "b", "children": [{"type": "t", "text": "S100A1's single cysteine is an indispensable redox switch for the protection against diastolic calcium waves in cardiomyocytes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Physiol Heart Circ Physiol (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1152/ajpheart.00634.2023"}], "href": "https://doi.org/10.1152/ajpheart.00634.2023"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38819384"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38819384"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Koichi Fukunaga, Makoto Arita, Minoru Takahashi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification and functional characterization of a presqualene diphosphate phosphatase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M512970200"}], "href": "https://doi.org/10.1074/jbc.M512970200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16464866"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16464866"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Troy Carlo, Nicos A Petasis, Bruce D Levy "}, {"type": "b", "children": [{"type": "t", "text": "Activation of polyisoprenyl diphosphate phosphatase 1 remodels cellular presqualene diphosphate."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochemistry (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1021/bi8020636"}], "href": "https://doi.org/10.1021/bi8020636"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19220020"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19220020"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Krystyna Teichert-Kuliszewska, James N Tsoporis, Jean-Francois Desjardins, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Absence of the calcium-binding protein, S100A1, confers pulmonary hypertension in mice associated with endothelial dysfunction and apoptosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cardiovasc Res (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/cvr/cvu241"}], "href": "https://doi.org/10.1093/cvr/cvu241"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25395393"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25395393"}]}]}]}