| http://purl.uniprot.org/citations/29760186 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
| http://purl.uniprot.org/citations/29760186 | http://www.w3.org/2000/01/rdf-schema#comment | "Mutations in thin filament regulatory proteins that cause hypertrophic cardiomyopathy (HCM) increase myofilament Ca2+ sensitivity. Mouse models exhibit increased Ca2+ buffering and arrhythmias, and we hypothesized that these changes are primary effects of the mutations (independent of compensatory changes) and that increased Ca2+ buffering and altered Ca2+ handling contribute to HCM pathogenesis via activation of Ca2+-dependent signaling. Here, we determined the primary effects of HCM mutations on intracellular Ca2+ handling and Ca2+-dependent signaling in a model system possessing Ca2+-handling mechanisms and contractile protein isoforms closely mirroring the human environment in the absence of potentially confounding remodeling. Using adenovirus, we expressed HCM-causing variants of human troponin-T, troponin-I, and α-tropomyosin (R92Q, R145G, and D175N, respectively) in isolated guinea pig left ventricular cardiomyocytes. After 48 h, each variant had localized to the I-band and comprised ∼50% of the total protein. HCM mutations significantly lowered the Kd of Ca2+ binding, resulting in higher Ca2+ buffering of mutant cardiomyocytes. We observed increased diastolic [Ca2+] and slowed Ca2+ reuptake, coupled with a significant decrease in basal sarcomere length and slowed relaxation. HCM mutant cells had higher sodium/calcium exchanger activity, sarcoplasmic reticulum Ca2+ load, and sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2) activity driven by Ca2+/calmodulin-dependent protein kinase II (CaMKII) phosphorylation of phospholamban. The ryanodine receptor (RyR) leak/load relationship was also increased, driven by CaMKII-mediated RyR phosphorylation. Altered Ca2+ homeostasis also increased signaling via both calcineurin/NFAT and extracellular signal-regulated kinase pathways. Altered myofilament Ca2+ buffering is the primary initiator of signaling cascades, indicating that directly targeting myofilament Ca2+ sensitivity provides an attractive therapeutic approach in HCM."xsd:string |
| http://purl.uniprot.org/citations/29760186 | http://purl.org/dc/terms/identifier | "doi:10.1074/jbc.ra118.002081"xsd:string |
| http://purl.uniprot.org/citations/29760186 | http://purl.uniprot.org/core/author | "Liu X."xsd:string |
| http://purl.uniprot.org/citations/29760186 | http://purl.uniprot.org/core/author | "Patel S."xsd:string |
| http://purl.uniprot.org/citations/29760186 | http://purl.uniprot.org/core/author | "Redwood C."xsd:string |
| http://purl.uniprot.org/citations/29760186 | http://purl.uniprot.org/core/author | "Watkins H."xsd:string |
| http://purl.uniprot.org/citations/29760186 | http://purl.uniprot.org/core/author | "Robinson P."xsd:string |
| http://purl.uniprot.org/citations/29760186 | http://purl.uniprot.org/core/author | "Zhang Y.H."xsd:string |
| http://purl.uniprot.org/citations/29760186 | http://purl.uniprot.org/core/author | "Casadei B."xsd:string |
| http://purl.uniprot.org/citations/29760186 | http://purl.uniprot.org/core/author | "Sparrow A."xsd:string |
| http://purl.uniprot.org/citations/29760186 | http://purl.uniprot.org/core/date | "2018"xsd:gYear |
| http://purl.uniprot.org/citations/29760186 | http://purl.uniprot.org/core/name | "J Biol Chem"xsd:string |
| http://purl.uniprot.org/citations/29760186 | http://purl.uniprot.org/core/pages | "10487-10499"xsd:string |
| http://purl.uniprot.org/citations/29760186 | http://purl.uniprot.org/core/title | "Hypertrophic cardiomyopathy mutations increase myofilament Ca2+ buffering, alter intracellular Ca2+ handling, and stimulate Ca2+-dependent signaling."xsd:string |
| http://purl.uniprot.org/citations/29760186 | http://purl.uniprot.org/core/volume | "293"xsd:string |
| http://purl.uniprot.org/citations/29760186 | http://www.w3.org/2004/02/skos/core#exactMatch | http://purl.uniprot.org/pubmed/29760186 |
| http://purl.uniprot.org/citations/29760186 | http://xmlns.com/foaf/0.1/primaryTopicOf | https://pubmed.ncbi.nlm.nih.gov/29760186 |
| http://purl.uniprot.org/uniprot/#_A0A0A0MRJ5-mappedCitation-29760186 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/29760186 |
| http://purl.uniprot.org/uniprot/#_A0A087WWU8-mappedCitation-29760186 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/29760186 |
| http://purl.uniprot.org/uniprot/#_Q15607-mappedCitation-29760186 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/29760186 |
| http://purl.uniprot.org/uniprot/#_Q15608-mappedCitation-29760186 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/29760186 |
| http://purl.uniprot.org/uniprot/#_A0A2R2Y2Q3-mappedCitation-29760186 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/29760186 |
| http://purl.uniprot.org/uniprot/#_A0A0S2Z4G4-mappedCitation-29760186 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/29760186 |
| http://purl.uniprot.org/uniprot/#_A0A0S2Z4G8-mappedCitation-29760186 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/29760186 |